Compound containing basic group and use thereof

ABSTRACT

The present invention relates to a compound represented by formula (I): 
     
       
         
         
             
             
         
       
     
     wherein all symbols are as defined here, a salt thereof, a solvate thereof, or a prodrug thereof. 
     The compound of the present invention has an antagonistic activity against CXCR4 and is therefore useful as a preventive and/or therapeutic agent for CXCR4-mediated diseases, for example, inflammatory and immune diseases (for example, rheumatoid arthritis, arthritis, retinopathy, pulmonary fibrosis, rejection of transplanted organ, etc.), allergic diseases, infections (for example, human immunodeficiency virus infection, acquired immunodeficiency syndrome, etc.), psychoneurotic diseases, cerebral diseases, cardiovascular disease, metabolic diseases, and cancerous diseases (for example, cancer, cancer metastasis, etc.), or an agent for regeneration therapy.

TECHNICAL FIELD

The present invention relates to compounds having a basic group which isuseful as medicaments, and use thereof.

More specifically, the present invention relates to (1) compoundsrepresented by formula (I):

wherein all symbols are as defined hereinafter, and salts thereof,N-oxides thereof or solvates thereof or prodrugs thereof, (2) usethereof, and (3) a method for producing the same.

BACKGROUND ART

Chemokine is known as a basic protein which has chemotaxis and anactivating effect on endogenous leucocytes and also has strongheparin-binding abilities. It is now considered that chemokine isassociated with not only control of infiltration of specific leucocytesupon inflammatory and immune responses, but also development, homing oflymphocytes under physiological conditions and migration of hemocyteprecursor cells and somatic cells.

Differentiation, proliferation and cell death of blood cells arecontrolled by various cytokines. Inflammation occurs at a local regionin a living body. Differentiation and maturation of lymphocytes, and thelike are carried out at a specific site. More particularly, requiredvarious cells migrate and accumulate in the specific site and a sequenceof inflammatory and immune responses arise. Thus, as well asdifferentiation, proliferation and death of cells, cell migration isalso an essential phenomenon to an immune system.

In the living body, migration of blood cells start with shiftinghemopoiesis that started at AGM (Aorta Gonad Mesonephros) region viafetal liver to permanent hematopoiesis at bone marrow in a developmentcourse. Moreover, precursors of T cells and thymus dendritic cellsmigrate from fetal liver into bone marrow and then into the thymusgland. They differentiate under thymus environment. The T cells aresubjected to clonal selection migrates into secondary lymphoid tissues,where they contribute to immune responses in periphery. Skin Langerhanscells that caught antigen, thereby undergone activation anddifferentiation migrate to T cell region in a topical lymph node, wherethey activate naive T cells therein as dendritic cells. The memory Tcells again perform its homing into the lymph node via lymphatic andblood vessels. In addition, B cells, T cells in intestinal epithelia,yδT cells, NKT cells, and dendritic cells migrate from bone marrow notvia thymus, differentiate and contribute to immune responses.

Chemokine is very involved in these various cell migrations. Forexample, SDF-1 (Stromal cell derived factor-1) and its receptor, CXCR4also act on various immune- and inflammatory reactions. For example,they have been reported to be associated with accumulation andactivation of CD4+T cells in a synovial membrane from a human patientsuffering from rheumatoid arthritis (J. Immunol., 165, 6590-6598(2000)). In addition, in a CIA model mouse, CXCR4 inhibitor inhibitedaccumulation of leucocytes in a joint and dramatically reduced arthritisscore (J. Immunol., 167, 4648-4692 (2001)). In a mouse OVA-inducedairway hypersensitive model, an anti-CXCR4 antibody reduced the numberof eosinophiles accumulating in pulmonary interstitial tissues andprevented airway hypersensitivity (J. Immunol., 165, 499-508 (2000)).

There has been reported that SDF-1 and its receptor, CXCR4 play animportant role in maintaining hemopoietic stem cells in bone marrow J.Exp. Med., 185, 111-120 (1997), Blood, 97, 3354-3360 (2001)).Accordingly, control of SDF-1 and CXCR4 is expected to modulaterecruitment of hemopoietic stem cells to peripheral blood and is usefulfor peripheral blood stem cell transplantation and reproductiontransplantation treatment.

SDF-1 and CXCR4 are associated with infiltration of various cancer cellssuch as breast cancer, prostate cancer, and ovarian cancer (Nature, 410,50-56 (2001), Cancer Res., 62, 1832-1837 (2002), Cancer Res., 62,5930-5938 (2002)). In a model of a SCID mouse which is transferred ahuman breast cancer cell strain into, an anti-CXCR4 antibody preventedmetastasis of breast cancer cells to lung (Nature, 410, 50-56 (2001)).In human ovarian epithelial tumor, highly expression of SDF-1 promotesaccumulation of plasmacytoid dendritic cells and inhibits the act ofbone marrow dendritic cells associated with tumor immune and suppressestumor immune (Nat. Med., 12, 1339 (2001)). Moreover, SDF-1 is associatedwith proliferation and migration of non-Hodgkin's lymphoma cells, and ina model of a NOD/SCID mouse which is transferred a human non-Hodgkin'slymphoma cells into, an anti-CXCR4 antibody inhibited proliferation ofthe tumor cells and improved mouse mortality (Cancer Res., 62, 3106-3112(2002)).

SDF-1 and CXCR4 play an important role for formation of hippocampusdentate gyrus granulocyte, that is essential for memory and learning andare associated with development of a disease associated with adultplasticity and pathology of hippocampus, for example Alzheimer'sdisease, stroke and epilepsy (Development, 129, 4249-4260 (2002), Trendsin Neuroscience, 25, 548-549 (2002)).

SDF-1 and CXCR4 are essential for a function of self-reactive B cellsassociated with development of diabetes. In NOD mouse, an anti-SDF-1antibody reduced blood glucose level and the number of mature IgM+Bcells in a periphery tissue (Immunology, 107, 222-232 (2002)). In ahuman arteriosclerotic plaque, SDF-1 was highly expressed and activatedblood platelets (Circ. Res., 86, 131-138 (2000)).

SDF-1 and CXCR4 are involved in residence of hemopoietic stem cells andhemopoietic precursor cells in bone marrow. CXCR4 antagonist, AMD 3100in combination with G-CSF increased the numbers of hemopoietic stemcells and hemopoietic precursor cells in periphery blood (JournalExperimental Medicine, 2001, 1307-1318 (2005)).

In addition, the results of SDF-1/CXCR4 knock-out mice showed that SDF-1is essential for functions of central nervous system, heart and vesselsof gastrointestinal tract in addition to lymphocytes (Nature, 382,635-639 (1996), Nature, 393, 591-594 (1998), Nature, 393, 595-599(1998)). Accordingly, it may be associated with a disease of thesetissues.

Thus, chemokine receptors are expressed at various specific cells and ata specific time. They are largely associated with the control ofinflammatory- and immune-responses through a mechanism by which theireffector cells accumulate in a site where chemokine is produced.

Acquired immunodeficiency syndrome (also called AIDS) that caused byinfection of human immunodeficiency virus (hereinafter abbreviated toHIV) is one of diseases for which therapies are the most eagerly desiredlately. Once HIV infection has been established in a main target cell,CD4+ cell, HIV repetitively proliferates in a patient's body and in theevent deathly destroys T cells responsible for immunological functionsby necrosis. In this process, immunological functions are graduallydeteriorated, various immunocompromised states become to develop such asfever, diarrhea and swelling of a lymph node, and various opportunisticinfections such as carinii pneumonia are easily complicated. It is wellknown that such a state is the onset of AIDS and induces malignanttumors such as Kaposi's sarcoma and becomes severe.

Currently, various preventive and therapeutic treatments for AIDS aretried as follows: for example, (1) inhibition of HIV proliferation byadministration of reverse transcriptase inhibitors and proteaseinhibitors, and (2) prevention or alleviation of opportunisticinfections by administration of an immunostimulant, etc.

HIV mainly infects helper T cells which play a key role in the immunesystem. Since 1985, it has been known that in this process HIV utilizesa membrane protein CD4 that is expressed on the membrane of T cells(Cell, 52, 631 (1985)). CD4 molecule consists of 433 amino acid residuesand is expressed in macrophages, some B cells, vascular endothelialcells, Langerhans cells in skin tissues, dendritic cells located inlymphatic tissues, glia cells of central nervous system and the like inaddition to mature helper T cells. However, as it becomes obvious thatHIV infection cannot be established with only CD4 molecule, the possiblepresence of some factor that is responsible for infection of cell withHIV, other than CD4 molecule, has been suggested.

In 1996, a cell membrane protein called Fusin has been identified as afactor responsible for HIV infection other than a CD4 molecule (Science,272, 872 (1996)). This Fusin molecule has been demonstrated to be areceptor for SDF-1, namely, CXCR4. In addition, it has been shown thatSDF-1 specifically inhibits infection of T cell-directed (X4) HIV invitro (Nature, 382, 829 (1996), Nature, 382, 833 (1996)). This may beconsidered that SDF-1 binds to CXCR4 prior to HIV, thereby taking away ascaffold for infecting a cell from HIV resulting in inhibition of HIVinfection.

Also, at the same period, there has been found that another chemokinereceptor CCR5, that is a receptor for RANTES, MIP-1α, and MIP-1β, isutilized at infection of macrophage-directed (R5) HIV (Science, 272,1955 (1996)).

Accordingly, those which can compete with HIV for CXCR4 and CCR5 orthose which bind to a HIV virus and prevent for said virus from bindingto CXCR4 and CCR5 may be a HIV infection inhibitor. In addition, thereis a case where a low molecular weight compound discovered as a HIVinfection inhibitor was showed to be indeed an antagonist of CXCR4(Nature Medicine, 4, 72 (1998)).

As described above, compounds having an antagonistic activity againstCXCR4 is effective, such as, for prevention and/or treatment ofinflammatory and immune diseases, allergic diseases, infections(particularly HIV infection), and diseases associated with theinfection, psychoneurotic diseases, cerebral diseases, cardiovasculardiseases, metabolic diseases, cancerous diseases and the like. Also, thecompounds are useful for cell medical treatment and regenerationtherapy.

Heretofore, some compounds having an antagonistic activity against CXCR4have been reported. For example, it is disclosed that a compoundrepresented by formula (X):

A^(1X) and A^(2X) each independently represents a hydrogen atom, anoptionally substituted monocyclic or polycyclic heteroaromatic ring, oran optionally substituted monocyclic or polycyclic aromatic ring; G^(1X)represents a single bond or —CR^(2X)R^(3X)-; R^(1X), R^(2X) and R^(3X)represent an optionally substituted alkyl group having 1 to 6 carbonatom(s); W^(X) represents an optionally substituted alkylene grouphaving 1 to 7 carbon atom(s), an optionally substituted monocyclic orpolycyclic heteroaromatic ring, or an optionally substituted monocyclicor polycyclic aromatic ring; X^(X) represents -z^(1X)-CO-z^(2X)-; z^(1X)and z^(2X) each independently represents a single bond or NR^(13X);y^(X) represents —CO—; D^(1X) and D^(2X) each independently represents ahydrogen atom or -G^(2X)-R^(4X); G^(2X) represents an optionallysubstituted alkylene group having 1 to 15 carbon atom(s); R^(4X)represents a hydrogen atom, an optionally substituted monocyclic orpolycyclic heteroaromatic ring, or an optionally substituted monocyclicor polycyclic aromatic ring; n2X represents 0 to 4; n1X represents 0 to3; and B^(X) represents —NR^(6X)R^(7X), and only required portions wereextracted with respect to definition of each group), or apharmaceutically acceptable salt has an antagonistic activity againstCXCR4 (see WO2003/029218 pamphlet).

Also, it is disclosed that a compound represented by formula (Y):

wherein n1Y, n2Y and n3Y represent 0 to 3; R^(1Y), R^(2Y), R^(3Y),R^(4Y), R^(5Y) and R^(6Y) each independently represents a hydrogen atom,or an optionally substituted alkyl group having 1 to 15 carbon atom(s);A^(1Y) and A^(2Y) each independently represents an optionallysubstituted monocyclic or polycyclic heteroaromatic ring; WY representsan optionally substituted alkylene group having 1 to 15 carbon atom(s);X^(Y) represents O, CH₂, or NR^(11Y); D^(Y) represents-Q^(Y)-Y^(Y)—B^(Y); Q^(Y) represents a single bond or —CO— when X^(Y) isNR^(11Y); Y^(Y) represents —(CR^(18Y)R^(19Y))_(m3Y)-; R^(18Y) andR^(19Y) each independently represents a hydrogen atom, or an optionallysubstituted alkyl group having 1 to 15 carbon atom(s); m3Y represents 0to 6; B^(Y) represents —NR^(25Y)R^(26Y); and R^(25Y) and R^(26Y)represent a hydrogen atom or an optionally substituted alkyl grouphaving 1 to 15 carbon atom(s) when X^(Y) is not CH₂, and only requiredportions were extracted with respect to definition of each group), or apharmaceutically acceptable salt or a prodrug thereof has anantagonistic activity against CXCR4 (see WO2004/024697 pamphlet).

Furthermore, it is disclosed that a compound represented by formula (Z):

wherein n1Z, n2Z and n3Z represent 0 to 3; R^(1Z), R^(2Z), R^(3Z),R^(4Z), R^(5Z) and R^(6Z) each independently represents a hydrogen atom,or an optionally substituted alkyl group having 1 to 15 carbon atom(s),and R^(5Z) and R^(6Z) may form a carbonyl group together with a carbonatom; A^(1Z) and A^(2Z) each independently represents an optionallysubstituted monocyclic or polycyclic heteroaromatic ring; W^(Z)represents an optionally substituted benzene ring; X^(Z) represents O,CH₂, or NR^(11Z); D^(Z) represents -Q^(Z)-Y^(Z)—B^(Z); Q^(Z) representsa single bond, —CO—, —CONH—, or NR^(12Z) when X^(Z) is CH₂; Y^(Z)represents —(CR^(18Z)R^(19Z))_(m3z)-; R^(18z) and R^(19z) eachindependently represents a hydrogen atom, or an optionally substitutedalkyl group having 1 to 15 carbon atom(s); m3Z represents 0 to 6; B^(Z)represents —NR^(25Z)R^(26Z); and R^(25Z) and R^(26Z) represent ahydrogen atom, or an optionally substituted alkyl group having 1 to 15carbon atom(s) when X^(Z) is not CH₂, and only required portions wereextracted with respect to definition of each group), or apharmaceutically acceptable salt or a prodrug thereof has anantagonistic activity against CXCR4 (se WO2005/085209 pamphlet).

Patent Literature 1 WO2003/029218 pamphlet Patent Literature 2WO2004/024697 pamphlet Patent Literature 3 WO2005/085209 pamphlet

DISCLOSURE OF THE INVENTION

It is earnestly desired to develop a CXCR4 antagonist which is useful asa preventive and/or therapeutic agent for inflammatory and immunediseases (for example, rheumatoid arthritis, arthritis, retinopathy,pulmonary fibrosis, rejection of transplanted organ, etc.), allergicdiseases, infections (for example, human immunodeficiency virusinfection, acquired immunodeficiency syndrome, etc.), and cancerousdiseases (for example, cancer, cancer metastasis, etc.), or an agent forregeneration therapy, and also causes less side effect and is safe.

The present inventors have intensively studied and found that a compoundrepresented by formula (I) described hereinafter surprisingly has astrong antagonistic activity against CXCR4, and thus the presentinvention has been completed.

The present invention relates to

[1] A compound represented by formula (I):

wherein A¹ and A² each independently represents a group having a basicgroup;

B¹ and B² each independently represents a bond, or a spacer having amain chain of 1 to 4 atom(s);

E represents a spacer having a main chain of 1 to 10 atom(s);

L represents a bond, or a spacer having a main chain of 1 to 4 atom(s);

J represents (1) an aliphatic hydrocarbon group which is substitutedwith a group having a basic group, and also may have a substituent(s),(2) a monocyclic or condensed cyclic group which is substituted with agroup having a basic group, and also may have a substituent(s), (3) aspiro-bound cyclic group which may be substituted with a group having abasic group, and also may have a substituent(s), or (4) a bridged cyclicgroup which may be substituted with a group having a basic group, andalso may have a substituent(s);

G represents G^(A) or G^(1A)-G^(2A)-G^(3A);

G^(A) represents a bond, a carbon atom which may have a substituent(s),or a nitrogen atom which may have a substituent;

G^(1A) represents a carbon atom which may have a substituent(s);

G^(2A) represents a carbon atom which may have a substituent(s), anitrogen atom which may have a substituent, an optionally oxidizedsulfur atom or an oxygen atom;

G^(3A) represents a bond, or a carbon atom which may have asubstituent(s); and

R represents a hydrogen atom, or a substituent), a salt thereof, asolvate thereof, or a prodrug thereof;

[2] The compound according to the above-described [1], wherein R is ahydrogen atom, a salt thereof, a solvate thereof, or a prodrug thereof;[3] The compound according to the above-described [1], wherein A¹ and A²each independently represents a nitrogen-containing heterocyclic ringwhich may have a substituent(s), a salt thereof, a solvate thereof, or aprodrug thereof;[4] The compound according to the above-described [3], wherein thenitrogen-containing heterocyclic ring is an imidazole ring, abenzoimidazole ring, or a pyridine ring, a salt thereof, a solvatethereof, or a prodrug thereof;[5] The compound according to the above-described [1], wherein thespacer having a main chain of 1 to 4 atom(s) represented by B¹ and B² is—CH₂—, a salt thereof, a solvate thereof, or a prodrug thereof;[6] The compound according to the above-described [1], wherein G is—CO—, —CH₂—, —CH(OH)—, or —NH—, a salt thereof, a solvate thereof, or aprodrug thereof;[7] The compound according to the above-described [1], wherein E is abenzene ring or a cyclohexane ring, a salt thereof, a solvate thereof,or a prodrug thereof;[8] The compound according to the above-described [1], wherein L is—CH₂— or —CH₂—NH— (provided that a nitrogen atom is bonded to J), a saltthereof, a solvate thereof, or a prodrug thereof;[9] The compound according to the above-described [1], wherein J is (3)a spiro-bound cyclic group which may be substituted with a group havinga basic group, and also may have a substituent(s), or (4) a bridgedcyclic group which may be substituted with a group having a basic group,and also may have a substituent(s), a salt thereof, a solvate thereof,or a prodrug thereof;[10] The compound according to the above-described [9], wherein J is aspiro-bound polycyclic heterocyclic ring or bridged polycyclicheterocyclic ring, which has at least one nitrogen atom, and also mayhave an oxygen atom(s) and/or an optionally oxidized sulfur atom(s) andwhich may be substituted with a group having a basic group, and also mayhave a substituent(s), a salt thereof, a solvate thereof, or a prodrugthereof;[11] The compound according to the above-described [9], wherein thespiro-bound polycyclic heterocyclic ring or bridged polycyclicheterocyclic ring which has at least one nitrogen atom, and also mayhave an oxygen atom and/or an optionally oxidized sulfur atom is:

wherein the nitrogen atom of —NH— may have a substituent(s), a saltthereof, a solvate thereof, or a prodrug thereof;[12] The compound according to the above-described [10], wherein thespiro-bound polycyclic heterocyclic ring is a 7- to 15-memberedspiro-bound bicyclic heterocyclic ring which consists of (i) amonocyclic ring composed of at least one nitrogen atom and carbon atomsand/or (ii) a monocyclic ring composed of at least one nitrogen atom,one oxygen atom and carbon atoms, a salt thereof, a solvate thereof, ora prodrug thereof;[13] The compound according to the above-described [12], wherein the 7-to 15-membered spiro-bound bicyclic heterocyclic ring is:

wherein the nitrogen atom of —NH— may have a substituent(s), a saltthereof, a solvate thereof, or a prodrug thereof;[14] The compound according to the above-described [1], wherein formula(I) is formula (I-1):

wherein ring A^(1A) and ring A^(2A) each independently represents animidazole ring which may have a substituent(s), a benzoimidazole ringwhich may have a substituent(s), or a pyridine ring which may have asubstituent(s),

G¹ represents —CO—, —CH₂—, —CH(OH)—, or —NH—, and

ring E¹ represents a 3- to 8-membered monocyclic group which may have asubstituent(s), and other symbols are as defined in the above-described[1], a salt thereof, a solvate thereof, or a prodrug thereof;

[15] The compound according to the above-described [14], wherein

wherein L^(A) represents (a)—(an aliphatic hydrocarbon having 1 to 3carbon atoms(s) which may have a substituent(s))—(a nitrogen atom whichmay have a substituent)-, or (b) a divalent aliphatic hydrocarbon having1 to 4 carbon atoms(s) which may have a substituent(s),

(a) when L^(A) is —(an aliphatic hydrocarbon having 1 to 3 carbonatoms(s) which may have a substituent(s))—(a nitrogen atom which mayhave a substituent)-, ring J¹ represents a 3- to 10-membered monocyclicor bicyclic heterocyclic ring composed of (i) a C3-10 monocyclic orbicyclic carbocyclic ring, or (ii) a 3- to 10-membered monocyclic orbicyclic heterocyclic ring composed of a carbon atom(s), an oxygenatom(s) and/or an optionally oxidized sulfur atom(s),

(b) when L_(A) is a divalent aliphatic hydrocarbon having 1 to 4 carbonatoms(s) which may have a substituent(s), ring J¹ represents a 3- to10-membered monocyclic or bicyclic heterocyclic ring which has at leastone nitrogen atom, and also may have an oxygen atom and/or an optionallyoxidized sulfur atom,

ring J² represents (i) a C3-10 monocyclic or bicyclic carbocyclic ringsubstituted with a group having a basic group, (ii) a 3- to 10-memberedmonocyclic or bicyclic heterocyclic ring composed of a carbon atom(s),an oxygen atom(s) and/or an optionally oxidized sulfur atom(s), which issubstituted with a group having a basic group, or (iii) a 3- to10-membered monocyclic or bicyclic heterocyclic ring which has at leastone nitrogen atom and also may have an oxygen atom or an optionallyoxidized sulfur atom, and also may be substituted with a group having abasic group,

ring J¹ and ring J² may have 1 to 8 substituent(s) on the substitutableposition and, when two or more substituents are present, pluralsubstituents may be the same or different,

wherein a nitrogen atom which may have a substituent in L_(A) is bondedto ring J¹, a salt thereof, a solvate thereof, or a prodrug thereof;

[16] The compound according to the above-described [15], wherein

wherein L_(A) is as defined in the above-described [15], wherein L_(A)may be bonded to the nitrogen atom of —NH— and the nitrogen atom of —NH—may have a substituent(s), a salt thereof, a solvate thereof, or aprodrug thereof;[17] The compound according to the above-described [1], wherein

wherein L_(A) is as defined in the above-described [15], wherein L_(A)may be bonded to the nitrogen atom of —NH— and the nitrogen atom of —NH—may have a substituent(s), a salt thereof, a solvate thereof, or aprodrug thereof;[18] The compound according to the above-described [1], wherein formula(I) is formula (I-4):

wherein ring E² represents a benzene ring which may have asubstituent(s), a cyclohexane ring which may have a substituent(s), acyclopentane ring which may have a substituent(s), a pyrrolidine ringwhich may have a substituent(s), or a piperidine ring which may have asubstituent(s);

R^(C) represents (1) a hydrogen atom, (2) cyano group, (3) a carboxylgroup which may be protected with a protective group, (4) a hydroxylgroup which may be protected with a protective group, (5) a C1-4 alkylgroup which may be substituted with a hydroxyl group which may beprotected with a protective group, or (6) an amino group which may beprotected with a protective group; and

-L^(B)-J^(B) represents (a)-L^(1B)J^(1B) wherein L^(1B) represents—CH₂—NH— or —CO—NH— (provided that the nitrogen atom is bonded toJ^(1B), and J^(1B) represents a C4-7 monocyclic carbocyclic ringsubstituted with a mono- or di-substituted amino group), or (b)

wherein L^(2B) represents a carbon atom which may have a substituent(s)and R¹ represents a hydrogen atom or a substituent), and other symbolsare as defined in the above-described [1] and [14], a salt thereof, asolvate thereof, or a prodrug thereof;[19] The compound according to the above-described [18], wherein theprotective group is a C1-4 alkyl group which may be substituted with anoxo group, a salt thereof, a solvate thereof, or a prodrug thereof;[20] The compound according to the above-described [18], wherein thesubstituent of the carbon atom which may have a substituent(s)represented by G^(1A) is absent, a hydroxyl group, an oxo group, or aC1-4 alkyl group, a salt thereof, a solvate thereof, or a prodrugthereof;[21] The compound according to the above-described [18], wherein G^(2A)is a nitrogen atom which may have a substituent and G^(3A) is a carbonatom which may have a substituent(s), a salt thereof, a solvate thereof,or a prodrug thereof;[22] The compound according to the above-described [21], wherein thesubstituent of the carbon atom which may have a substituent(s)represented by G^(2A) is (1) absent, (2) a C1-4 alkyl group, (3) a C1-4alkyl group substituted with a hydroxyl group which may be protectedwith a protective group, (4) a C1-4 alkyl group substituted with anamino group which may be protected with a protective group, (5) a C1-4alkyl group substituted with a carboxyl group which may be protectedwith a protective group, or (6) a C1-4 alkyl group substituted with apyrrolidine ring, a piperidine ring or a morpholine ring, a saltthereof, a solvate thereof, or a prodrug thereof;[23] The compound according to the above-described [22], wherein theprotective group is a C1-4 alkyl group which may be substituted with anoxo group, a salt thereof, a solvate thereof, or a prodrug thereof;[24] The compound according to the above-described [21], wherein thesubstituent of the carbon atom which may have a substituent(s)represented by G^(3A) is absent, a C1-4 alkyl group, a hydroxyl group oran oxo group, a salt thereof, a solvate thereof, or a prodrug thereof;[25] The compound according to the above-described [18], wherein-L^(B)-J^(B) is (a)-L^(1B)-J^(1B) (symbols in the group are as definedin the above-described [18]), a salt thereof, a solvate thereof, or aprodrug thereof;[26] The compound according to the above-described [18], wherein-L^(B)-J^(B) is (b)

wherein symbols are as defined in the above-described [18], a saltthereof, a solvate thereof, or a prodrug thereof;[27] The compound according to the above-described [18], wherein formula(I) is formula (I-4-a):

wherein G^(3B) represents —CH₂— or —CO—,

R^(1C) represents a hydrogen atom, a cyano group, a C1-4 alkyl groupsubstituted with a hydroxyl group, or a C1-4 alkyl group substitutedwith an acetyloxy group,

R² represents a hydrogen atom, or a hydroxyethyl, acetyl, methoxyethyl,pyrrolidinylethyl, morpholinylethyl, hydroxymethylcarbonyl,dimethylaminoethyl or acetylaminoethyl group, and R³ represents a C1-4alkyl group, a C5-7 saturated monocyclic carbocyclic ring or a(3-methyl-2-thienyl)methyl group), a salt thereof, a solvate thereof, ora prodrug thereof;

[28] The compound according to the above-described [1], wherein formula(I) is formula (I-5):

wherein R⁴ and R⁵ represent a hydrogen atom or a substituent and othersymbols are as defined in the above-described [14] and [18], a saltthereof, a solvate thereof, or a prodrug thereof;[29] The compound according to the above-described [1], wherein formula(I) is formula (I-6):

wherein R⁶ represents a hydrogen atom or a substituent and other symbolsare as defined in the above-described [14] and [18], a salt thereof, asolvate thereof, or a prodrug thereof;[30] The compound according to the above-described [1], which is

-   2-{4-[3-(1H-imidazol-2-yl)-2-(1H-imidazol-2-ylmethyl)propoxy]benzyl}-8-[(3-methyl-2-thienyl)methyl]-2,8-diazaspiro[4.5]decane,-   N-[3-(1H-imidazol-2-yl)-2-(1H-imidazol-2-ylmethyl)propyl]-N-[4-({8-[(3-methyl-2-thienyl)methyl]-2,8-diazaspiro[4.5]dec-2-yl}methyl)benzyl]acetoamide,-   8-cyclohexyl-2-{4-[3-(1H-imidazol-2-yl)-2-(1H-imidazol-2-ylmethyl)propyl]benzyl}-2,8-diazaspiro[4.5]decane,-   3-({4-[(8-cyclohexyl-2,8-diazaspiro[4.5]dec-2-yl)methyl]benzyl}amino)-2,2-bis(1H-imidazol-2-ylmethyl)-1-propanol,-   2-{{4-[(8-cyclohexyl-2,8-diazaspiro[4.5]dec-2-yl)methyl]benzyl}[3-(1H-imidazol-2-yl)-2-(1H-imidazol-2-ylmethyl)propyl]amino}ethanol,-   N-[2-cyano-3-(1H-imidazol-2-yl)-2-(1H-imidazol-2-ylmethyl)propyl]-N-{4-[(8-cyclohexyl-2,8-diazaspiro[4.5]dec-2-yl)methyl]benzyl}acetoamide,-   N-[3-(1H-imidazol-2-yl)-2-(1H-imidazol-2-ylmethyl)propyl]-4-[(8-isobutyl-2,8-diazaspiro[4.5]dec-2-yl)methyl]benzamide,-   N-[3-(1H-imidazol-2-yl)-2-(1H-imidazol-2-ylmethyl)propyl]-4-[(8-isobutyl-2,8-diazaspiro[4.5]dec-2-yl)methyl]-N-(2-methoxyethyl)benzamide,-   N-[3-(1H-imidazol-2-yl)-2-(1H-imidazol-2-ylmethyl)propyl]-4-[(8-isobutyl-2,8-diazaspiro[4.5]dec-2-yl)methyl]-N-[2-(1-pyrrolidinyl)ethyl]benzamide,-   2-hydroxy-N-[3-(1H-imidazol-2-yl)-2-(1H-imidazol-2-ylmethyl)propyl]-N-{4-[(8-isobutyl-2,8-diazaspiro[4.5]dec-2-yl)methyl]benzyl}acetoamide,-   N-[3-hydroxy-2,2-bis(1H-imidazol-2-ylmethyl)propyl]-N-{4-[(8-isobutyl-2,8-diazaspiro[4.5]dec-2-yl)methyl]benzyl}acetoamide,-   N-[2-(dimethylamino)ethyl]-N-[3-(1H-imidazol-2-yl)-2-(1H-imidazol-2-ylmethyl)propyl]-4-[(8-isobutyl-2,8-diazaspiro[4.5]dec-2-yl)methyl]benzamide,-   N-(2-acetoamideethyl)-N-[3-(1H-imidazol-2-yl)-2-(1H-imidazol-2-ylmethyl)propyl]-4-[(8-isobutyl-2,8-diazaspiro[4.5]dec-2-yl)methyl]benzamide,-   N-[3-(1H-imidazol-2-yl)-2-(1H-imidazol-2-ylmethyl)propyl]-4-[(8-isobutyl-2,8-diazaspiro[4.5]dec-2-yl)methyl]-N-[2-(4-morpholinyl)ethyl]benzamide,    or-   3-({4-[(8-cyclohexyl-2,8-diazaspiro[4.5]dec-2-yl)methyl]benzoyl}amino)-2,2-bis(1H-imidazol-2-ylmethyl)propyl    acetate, a salt thereof, a solvate thereof, or a prodrug thereof;    [31] A pharmaceutical composition comprising a compound represented    by formula (I) according to the above-described [1], a salt thereof,    a solvate thereof, or a prodrug thereof;    [32] The pharmaceutical composition according to the above-described    [31], which is a CXCR4 antagonist;    [33] The pharmaceutical composition according to the above-described    [31], which is preventive and/or therapeutic agent for    CXCR4-mediated diseases, or an agent for regeneration therapy;    [34] The pharmaceutical composition according to the above-described    [33], wherein the CXCR4-mediated disease is human immunodeficiency    virus infection, acquired immunodeficiency syndrome, cancer, cancer    metastasis, rheumatoid arthritis, arthritis, retinopathy, pulmonary    fibrosis or rejection of transplanted organ, or the agent for    regeneration therapy is an agent for transplantation medical    treatment;    [35] The pharmaceutical composition according to the above-described    [33], wherein the CXCR4-mediated disease is human immunodeficiency    virus infection;    [36] A medicament comprising a compound represented by formula (I)    according to the above-described [1], a salt thereof, a solvate    thereof, or a prodrug thereof, and one or more kinds selected from    reverse transcriptase inhibitor, protease inhibitor, CCR2    antagonist, CCR3 antagonist, CCR4 antagonist, CCR5 antagonist, CXCR4    antagonist, HIV integrase inhibitor, fusion inhibitor, CD4    antagonist, antibody against surface antigen of HIV, Short    Interfering RNA targeting a HIV-related factor, and vaccine of HIV;    [37] A method for antagonizing CXCR4 in a mammal, comprising    administering an effective dosage of a compound represented by    formula (I) according to the above-described [1], a salt thereof, a    solvate thereof, or a prodrug thereof to the mammal;    [38] A method of prevention and/or treatment for CXCR4-mediated    diseases in a mammal, comprising administering an effective dosage    of a compound represented by formula (I) according to the    above-described [1], a salt thereof, a solvate thereof, or a prodrug    thereof to the mammal;    [39] Use of a compound represented by formula (I) according to the    above-described [1], a salt thereof, a solvate thereof or a prodrug    thereof for production of a CXCR4 antagonist;    [40] Use of a compound represented by formula (I) according to the    above-described [1], a salt thereof, a solvate thereof or a prodrug    thereof for production of a preventive and/or therapeutic agent for    CXCR4-mediated diseases;    [41] The compound according to [14], wherein -L-J is

wherein ring J³ represents (i) a bridged polycyclic carbocyclic ringsubstituted with a group having a basic group, (ii) a bridged polycyclicheterocyclic ring composed of a carbon atom(s), an oxygen atom(s) and/oran optionally oxidized sulfur atom(s), which is substituted with a grouphaving a basic group, or (iii) a bridged polycyclic heterocyclic ringwhich has at least one nitrogen atom and also may have an oxygen atom(s)and/or an optionally oxidized sulfur atom(s), and which may besubstituted with a group having a basic group,

ring J³ may have 1 to 8 substituent(s) on the substitutable positionand, when two or more substituents are present, plural substituents maybe the same or different, and L^(A) is as defined in [15];

[42] The compound according to [14], wherein -L-J is

wherein ring J⁴ represents (i) a C3-15 monocyclic or condensedcarbocyclic ring substituted with a group having a basic group, (ii) a3- to 15-membered monocyclic or condensed heterocyclic ring composed ofa carbon atom, an oxygen atom and/or an optionally oxidized sulfur atom,which is substituted with a group having a basic group, or (iii) a 3- to15-membered monocyclic or condensed heterocyclic ring which has at leastone nitrogen atom and also may have an oxygen atom and/or an optionallyoxidized sulfur atom, and which may be substituted with a group having abasic group,

ring J⁴ may have 1 to 8 substituent(s) on the substitutable positionand, when two or more substituents are present, plural substituents maybe the same or different, and L_(A) is as defined in [15]; and

[43] A method for producing a compound represented by formula (I), asalt thereof, an N-oxide thereof or a solvate thereof, or a prodrugthereof.

EFFECT OF THE INVENTION

The compound of the present invention has an antagonistic activityagainst CXCR4 and is therefore useful as a preventive and/or therapeuticagent for diseases associated with CXCR4, namely, CXCR4-mediateddiseases.

BEST MODE FOR CARRYING OUT THE INVENTION

In the present specification, “bond” means to directly bind withoutmediating the other atom therebetween.

In the present specification, “cyclic group” includes, for example, amonocyclic or condensed ring, a bridged ring, a spiro-bound ring and thelike. This “monocyclic or condensed ring” includes, for example, a C3-15monocyclic or condensed carbocyclic ring, a 3- to 15-membered monocyclicor condensed heterocyclic ring having, as a heteroatom, 1 to 4 nitrogenatom(s), 1 to 2 oxygen atom(s) and/or 1 to 2 sulfur atom(s) and thelike. The “C3-15 monocyclic or condensed carbocyclic ring” includes aC3-15 monocyclic or condensed unsaturated carbocyclic ring, or partiallyor completely saturated one thereof. Examples of the “C3-15 monocyclicor condensed unsaturated carbocyclic ring, or partially or completelysaturated one thereof” include, for example, cyclopropane, cyclobutane,cyclopentane, cyclohexane, cycloheptane, cyclooctane, cyclononane,cyclodecane, cycloundecane, cyclododecane, cyclotridecane,cyclotetradecane, cyclopentadecane, cyclopentene, cyclohexene,cycloheptene, cyclooctene, cyclopentadiene, cyclohexadiene,cycloheptadiene, cyclooctadiene, benzene, pentalene, perhydropentalene,azulene, perhydroazulene, indene, perhydroindene, indane, naphthalene,dihydronaphthalene, tetrahydronaphthalene, perhydronaphthalene,heptalene, perhydroheptalene, biphenylene, as-indacene, s-indacene,acenaphthylene, acenaphthene, fluorene, phenalene, phenanthrene,anthracene, and 1,2,3,5,6,7-hexahydro-s-indacene rings. Among these,examples of the “C3-15 monocyclic or condensed aromatic carbocyclicring” include benzene, azulene, naphthalene, phenanthrene, anthracenerings and the like.

Examples of the “3- to 15-membered monocyclic or condensed heterocyclicring having, as a heteroatom, 1 to 4 nitrogen atom(s), 1 to 2 oxygenatom(s) and/or 1 to 2 sulfur atom(s)” include a 3- to 15-memberedmonocyclic or condensed unsaturated heterocyclic ring having, as aheteroatom, 1 to 4 nitrogen atom(s), 1 to 2 oxygen atom(s) and/or 1 to 2sulfur atom(s), or partially or completely saturated one thereof.Examples of the “3- to 15-membered monocyclic or condensed unsaturatedheterocyclic ring having, as a heteroatom, 1 to 4 nitrogen atom(s), 1 to2 oxygen atom(s) and/or 1 to 2 sulfur atom(s), or partially orcompletely saturated one thereof” include, for example, pyrrole,imidazole, triazole, tetrazole, pyrazole, pyridine, pyrazine,pyrimidine, pyridazine, azepine, diazepine, furan, pyran, oxepine,thiophene, thiopyran, thiepine, oxazole, isoxazole, thiazole,isothiazole, furazan, oxadiazole, oxazine, oxadiazine, oxazepine,oxadiazepine, thiadiazole, thiazine, thiadiazine, thiazepine,thiadiazepine, indole, isoindole, indolizine, benzofuran, isobenzofuran,benzothiophene, isobenzothiophene, dithianaphthalene, indazole,quinoline, isoquinoline, quinolizine, purine, phthalazine, pteridine,naphthyridine, quinoxaline, quinazoline, cinnoline, benzoxazole,benzothiazole, benzimidazole, chromene, benzoxepine, benzoxazepine,benzoxadiazepine, benzothiepine, benzothiazepine, benzothiadiazepine,benzoazepine, benzodiazepine, benzofurazan, benzothiadiazole,benzotriazole, carbazole, β-carboline, acridine, phenazine,dibenzofuran, xanthene, dibenzothiophene, phenothiazine, phenoxazine,phenoxathiin, thianthrene, phenanthridine, phenanthroline, perimidine,aziridine, azetidine, pyrroline, pyrrolidine, imidazoline,imidazolidine, triazoline, triazolidine, tetrazoline, tetrazolidine,pyrazoline, pyrazolidine, dihydropyridine, tetrahydropyridine,piperidine, dihydropyrazine, tetrahydropyrazine, piperazine,dihydropyrimidine, tetrahydropyrimidine, perhydropyrimidine,dihydropyridazine, tetrahydropyridazine, perhydropyridazine,dihydroazepine, tetrahydroazepine, perhydroazepine, dihydrodiazepine,tetrahydrodiazepine, perhydrodiazepine, oxirane, oxetane, dihydrofuran,tetrahydrofuran, dihydropyran, tetrahydropyran, dihydrooxepine,tetrahydrooxepine, perhydrooxepine, thiirane, thietane,dihydrothiophene, tetrahydrothiophene, dihydrothiopyran,tetrahydrothiopyran, dihydrothiepine, tetrahydrothiepine,perhydrothiepine, dihydrooxazole, tetrahydrooxazole (oxazolidine),dihydroisoxazole, tetrahydroisoxazole (isoxazolidine), dihydrothiazole,tetrahydrothiazole (thiazolidine), dihydroisothiazole,tetrahydroisothiazole (isothiazolidine), dihydrofurazan,tetrahydrofurazan, dihydrooxadiazole, tetrahydrooxadiazole(oxadiazolidine), dihydrooxazine, tetrahydrooxazine, dihydrooxadiazine,tetrahydrooxadiazine, dihydrooxazepine, tetrahydrooxazepine,perhydrooxazepine, dihydrooxadiazepine, tetrahydrooxadiazepine,perhydrooxadiazepine, dihydrothiadiazole, tetrahydrothiadiazole(thiadiazolidine), dihydrothiazine, tetrahydrothiazine,dihydrothiadiazine, tetrahydrothiadiazine, dihydrothiazepine,tetrahydrothiazepine, perhydrothiazepine, dihydrothiadiazepine,tetrahydrothiadiazepine, perhydrothiadiazepine, morpholine,thiomorpholine, oxathiane, indoline, isoindoline, dihydrobenzofuran,perhydrobenzofuran, dihydroisobenzofuran, perhydroisobenzofuran,dihydrobenzothiophene, perhydrobenzothiophene, dihydroisobenzothiophene,perhydroisobenzothiophene, dihydroindazole, perhydroindazole,dihydroquinoline, tetrahydroquinoline, perhydroquinoline,dihydroisoquinoline, tetrahydroisoquinoline, perhydroisoquinoline,dihydrophthalazine, tetrahydrophthalazine, perhydrophthalazine,dihydronaphthyridine, tetrahydronaphthyridine, perhydronaphthyridine,dihydroquinoxaline, tetrahydroquinoxaline, perhydroquinoxaline,dihydroquinazoline, tetrahydroquinazoline, perhydroquinazoline,dihydrocinnoline, tetrahydrocinnoline, perhydrocinnoline, benzoxathiane,dihydrobenzoxazine, dihydrobenzothiazine, pyrazinomorpholine,dihydrobenzoxazole, perhydrobenzoxazole, dihydrobenzothiazole,perhydrobenzothiazole, dihydrobenzimidazole, perhydrobenzimidazole,dihydrobenzazepine, tetrahydro benzoazepin, dihydrobenzodiazepine,tetrahydrobenzodiazepine, benzodioxepane, dihydrobenzoxazepine,tetrahydrobenzoxazepine, dihydrocarbazole, tetrahydrocarbazole,perhydrocarbazole, dihydroacridine, tetrahydroacridine,perhydroacridine, dihydrodibenzofuran, dihydrodibenzothiophene,tetrahydrodibenzofuran, tetrahydrodibenzothiophene,perhydrodibenzofuran, perhydrodibenzothiophene, dioxolane, dioxane,dithiolane, dithiane, dioxaindane, benzodioxane, chroman,benzodithiolane, benzodithiane, 6,7-dihydro-5H-cyclopenta[b]pyrazine,5H-cyclopenta[b]pyrazine, imidazo[2,1-b][1,3]thiazole,pyrido[2,3-b]pyrazine, pyrido[3,4-b]pyrazine,[1,3]thiazolo[4,5-b]pyrazine, thieno[2,3-b]pyrazine,3,4-dihydro-2H-pyrazino[2,3-b][1,4]oxazine,6,7-dihydro-5H-cyclopenta[b]pyrazine, imidazo[1,2-a]pyrazine,6,7-dihydro-5H-cyclopenta[b]pyridine, furo[3,2-b]pyridine,pyrido[2,3-d]pyrimidine, 2,3-dihydro-1H-pyrrolo[2,3-b]pyridine,5,6,7,8-tetrahydro-1,6-naphthylidine,6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine,3,4-dihydro-2H-pyrano[3,2-c]pyridine, 2,3-dihydrofuro[3,2-c]pyridine,hexahydro-1H-pyrrolidine, octahydrocyclopenta[c]pyrrole,octahydrocyclopenta[b]pyrrole, octahydropyrrolo[3,2-b]pyrrole,octahydropyrrolo[3,4-c]pyrrole, hexahydro-2H-furo[3,2-b]pyrrole,hexahydro-2H-thieno[3,2-b]pyrrole, decahydroquinoline,decahydro-2,6-naphthylidine, octahydro-2H-quinolidine,octahydro-1H-pyrido[1,2-c]pyrimidine, octahydro-2H-1,4-benzooxazine,decahydro-1,5-naphthylidine, octahydro-1H-pyrrolo[3,4-b]pyridine,octahydro-1H-pyrrolo[3,4-c]pyridine rings and the like. Among these,examples of the “3- to 15-membered monocyclic or condensed heterocyclicring having, as a heteroatom, 1 to 4 nitrogen atom(s), 1 to 2 oxygenatom(s) and/or 1 to 2 sulfur atom(s)” include pyrrole, imidazole,triazole, tetrazole, pyrazole, pyridine, pyrazine, pyrimidine,pyridazine, furan, thiophene, oxazole, isoxazole, thiazole, isothiazole,furazan, oxadiazole, thiadiazole, indole, isoindole, benzofuran,isobenzofuran, benzothiophene, isobenzothiophene, indazole, quinoline,isoquinoline, purine, phthalazine, pteridine, naphthylidine,quinoxaline, quinazoline, cinnoline, benzoxazole, benzothiazole,benzimidazole, benzofurazan, benzothiadiazole, benzotriazole, carbazole,β-carboline, acridine, phenazine, dibenzofuran, dibenzothiophene,phenanthridine, phenanthroline, perimidine rings and the like.

The “bridged ring” includes a bridged polycyclic carbocyclic ring and abridged polycyclic heterocyclic ring. The “bridged polycycliccarbocyclic ring” includes, for example, a C4-15 bridged polycycliccarbocyclic ring. Examples of the “C4-15 bridged polycyclic carbocyclicring” include bicyclo[2.2.1]heptane, bicyclo[2.2.1]hept-2-ene,bicyclo[3.1.1]heptane, bicyclo[3.1.1]hept-2-ene, bicyclo[3.2.1]octane,bicyclo[2.2.2]octane, bicyclo[2.2.2]oct-2-ene, adamantane,noradamantane, bicyclo[2.1.1]hexane, bicyclo[3.3.1]nonane,bicyclo[3.2.1]octane, bicyclo[3.3.2]decane ring and the like.

Examples of the “bridged polycyclic heterocyclic ring” include, forexample, a polycyclic heterocyclic bridged ring having, as a heteroatom,1 to 4 nitrogen atom(s), 1 to 2 oxygen atom(s) and/or 1 to 2 sulfuratom(s). Examples of the “polycyclic heterocyclic bridged ring having,as a heteroatom, 1 to 4 nitrogen atom(s), 1 to 2 oxygen atom(s) and/or 1to 2 sulfur atom(s)” include, for example, a “4- to 15-memberedpolycyclic heterocyclic bridged ring having, as a heteroatom, 1 to 4nitrogen atom(s), 1 to 2 oxygen atom(s) and/or 1 to 2 sulfur atom(s)”.Examples of the “4- to 15-membered polycyclic heterocyclic bridged ringhaving, as a heteroatom, 1 to 4 nitrogen atom(s), 1 to 2 oxygen atom(s)and/or 1 to 2 sulfur atom(s)” include azabicyclo[2.2.1]heptane,oxabicyclo[2.2.1]heptane, azabicyclo[3.1.1]heptane,azabicyclo[3.2.1]octane, oxabicyclo[3.2.1]octane,azabicyclo[2.2.2]octane, diazabicyclo[2.2.2]octane,1-azatricyclo[3.3.1.1^(3,7)]decane, 3-azabicyclo[3.3.1]nonane,3,7-diazabicyclo[3.3.1]nonane rings and the like.

The “spiro-bound ring” includes a spiro-bound polycyclic carbocyclicring and a spiro-bound polycyclic heterocyclic ring. Examples of the“spiro-bound polycyclic carbocyclic ring” include spiro[4.4]nonane,spiro[4.5]decane, spiro[5.5]undecane, spiro[3.4]octane, spiro[3.5]nonanerings and the like.

The “spiro-bound polycyclic heterocyclic ring” includes a spiro-boundpolycyclic heterocyclic ring having, as a heteroatom, 1 to 4 nitrogenatom(s), 1 to 2 oxygen atom(s) and/or 1 to 2 sulfur atom(s). The“spiro-bound polycyclic heterocyclic ring having, as a heteroatom, 1 to4 nitrogen atom(s), 1 to 2 oxygen atom(s) and/or 1 to 2 sulfur atom(s)”include a 7- to 15-membered spiro-bound polycyclic heterocyclic ringhaving, as a heteroatom, 1 to 4 nitrogen atom(s), 1 to 2 oxygen atom(s)and/or 1 to 2 sulfur atom(s). Examples of the “7- to 15-memberedspiro-bound polycyclic heterocyclic ring having, as a heteroatom, 1 to 4nitrogen atom(s), 1 to 2 oxygen atom(s) and/or 1 to 2 sulfur atom(s)”herein include azaspiro[4.4]nonane, oxazaspiro[4.4]nonane,dioxaspiro[4.4]nonane, azaspiro[4.5]decane, thiaspiro[4.5]decane,dithiaspiro[4.5]decane, dioxaspiro[4.5]decane, oxazaspiro[4.5]decane,azaspiro[5.5]undecane, oxaspiro[5.5]undecane, dioxaspiro[5.5]undecane,2,7-diazaspiro[3.5]nonane, 2,8-diazaspiro[4.5]decane,2,7-diazaspiro[4.5]decane, 2,9-diazaspiro[5.5]undecane,2,8-diazaspiro[5.5]undecane, 3,9-diazaspiro[5.5]undecane,2,7-diazaspiro[4.4]nonane, 1,2-dihydrospiro[indole-3,4′-piperidine],2,3-dihydro-1H-spiro[isoquinoline-4,4′-piperidine],1′,4′-dihydro-2′H-spiro[piperidine-4,3′-quinoline],2′,3′-dihydro-1′H-spiro[piperidine-4,4′-quinoline],8-azaspiro[4.5]decane, 7-azaspiro[4.5]decane, 3-azaspiro[5.5]undecane,2-azaspiro[5.5]undecane, 1-oxa-4,8-diazaspiro[5.5]undecane,1-oxa-4,9-diazaspiro[5.5]undecane,3,4-dihydrospiro[chromene-2,4′-piperidine], 2-azaspiro[4.4]nonane,7-azaspiro[3.5]nonane, 2,3-dihydrospiro[indene-1,4′-piperidine],3,4-dihydro-2H-spiro[naphthalene-1,4′-piperidine],3,4-dihydro-1H-spiro[naphthalene-2,4′-piperidine],2-azaspiro[4.5]decane, 2-azaspiro[3.5]nonane,1′,2′-dihydrospiro[cyclohexane-1,3′-indole],2′,3′-dihydro-1′H-spiro[cyclohexane-1,4′-isoquinoline],1′,4′-dihydro-2′H-spiro[cyclohexane-1,3′-quinoline],1,6-diazaspiro[3.4]octane, 1,5-diazaspiro[3.4]octane,1,7-diazaspiro[3.5]nonane, 1,6-diazaspiro[3.5]nonane,1,5-diazaspiro[3.5]nonane, 1,7-diazaspiro[4.4]nonane,1,6-diazaspiro[4.4]nonane, 1,8-diazaspiro[4.5]decane,1,7-diazaspiro[4.5]decane, 2,6-diazaspiro[3.4]octane,1,6-diazaspiro[4.5]decane, 2,6-diazaspiro[3.5]nonane,1,9-diazaspiro[5.5]undecane, 1,8-diazaspiro[5.5]undecane,6-azaspiro[3.5]nonane, 6-azaspiro[3.4]octane, 2-azaspiro[3.4]octane,1,7-diazaspiro[5.5]undecane, 1,4,9-triazaspiro[5.5]undecane,1,3,8-triazaspiro[4.5]decane, 1-thia-4,9-diazaspiro[5.5]undecane,1-thia-4,8-diazaspiro[5.5]undecane rings and the like.

In the present specification, “aliphatic hydrocarbon group” includes,for example, “linear or branched aliphatic hydrocarbon group”. Examplesof the “linear or branched aliphatic hydrocarbon group” include“aliphatic hydrocarbon group having 1 to 8 carbon atom(s)”, and examplesof “aliphatic hydrocarbon group having 1 to 8 carbon atom(s)” includeC1-8 alkyl group, C2-8 alkenyl group, and C2-8 alkynyl group.

Examples of the C1-8 alkyl group include methyl, ethyl, propyl, butyl,pentyl, hexyl, heptyl, and octyl groups, and isomer groups thereof. Theisomer groups of propyl include, for example, isopropyl and the isomergroups of butyl include, for example, sec-butyl, tert-butyl.

Examples of the C2-8 alkenyl group include vinyl, propenyl, butenyl,pentenyl, hexenyl, heptenyl, octenyl, butadienyl, pentadienyl,hexadienyl, heptadienyl, octadienyl, hexatrienyl, heptatrienyl, andoctatrienyl groups, and isomer groups thereof.

Examples of the C2-8 alkynyl group include ethynyl, propynyl, butynyl,pentynyl, hexynyl, heptynyl, octynyl, butadiynyl, pentadiynyl,hexadiynyl, heptadiynyl, octadiynyl, hexatriynyl, heptatriynyl, andoctatriynyl groups, and isomer groups thereof.

Examples of the C1-4 alkyl group include methyl, ethyl, propyl,isopropyl, butyl, sec-butyl, and tert-butyl group.

In the present specification, “group having a basic group” representedby A¹ and A² is not specifically limited as long as it has a basicgroup. Examples thereof include (1) basic group, (2) aliphatichydrocarbon group which is substituted with a basic group, and also mayhave a substituent(s), and (3) cyclic group which is substituted with abasic group, and also may have a substituent(s).

The “aliphatic hydrocarbon group” in the “aliphatic hydrocarbon groupwhich is substituted with a basic group, and also may have asubstituent(s)” has the same meaning as in the aliphatic hydrocarbongroup.

The “cyclic group” in the “cyclic group which is substituted with abasic group, and also may have a substituent(s)” has the same meaning asin the cyclic group.

The “substituent” in the “aliphatic hydrocarbon group which issubstituted with a basic group, and also may have a substituent(s)” orthe “cyclic group which is substituted with a basic group, and also mayhave a substituent(s)” is not specifically limited as long as it is asubstituent. Examples thereof include the following substituents definedas T.

Examples of T include:

(1) aliphatic hydrocarbon group,(2) C1-8 alkylidene group (for example, methylidene, ethylidene,propylidene, butylidene, pentylidene, hexylidene, heptylidene, oroctylidene group, and isomer thereof, etc.),(3) cyclic group,(4) aliphatic hydrocarbon group substituted with a cyclic group (forexample, cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl,phenylmethyl, naphthyl methyl, pyridinyl methyl, cyclopropyl ethyl,cyclopentylethyl, cyclohexylethyl, phenylethyl, naphthylethyl,pyridinylethyl, cyclopropylpropyl, cyclopentylpropyl, cyclohexylpropyl,phenylmethyl, phenylpropyl, naphthylpropyl, pyridinylpropyl, etc.),(5) hydroxyl group,(6) —O-aliphatic hydrocarbon group (for example, methoxy, ethoxy,propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, pentoxy, hexyloxy,heptyloxy, octyloxy, propenyloxy, butenyloxy, pentenyloxy, hexenyloxy,propynyloxy, butynyloxy, pentynyloxy, hexynyloxy, etc.),(7) —O-cyclic group (for example, cyclopropyloxy, cyclopentyloxy,cyclohexyloxy, phenoxy, naphthyloxy, pyridinyloxy, etc.),(8) —O-aliphatic hydrocarbon-cyclic group (for example,cyclopentylmethoxy, cyclohexylmethoxy, phenylmethoxy, etc.),(9) mercapto group,(10) —S-aliphatic hydrocarbon group (for example, methylthio, ethylthio,propylthio, isopropylthio, butylthio, isobutylthio, tert-butylthio,pentylthio, hexylthio, heptylthio, octylthio, propenylthio, butenylthio,pentenylthio, hexenylthio, propynylthio, butynylthio, pentynylthio,hexynylthio, etc.),(11) —S-cyclic group (for example, cyclopropylthio, cyclopentylthio,cyclohexylthio, phenylthio, naphthylthio, pyridinylthio, etc.),(12) —S-aliphatic hydrocarbon-cyclic group (for example,cyclopentylmethylthio, cyclohexylmethylthio, phenylmethylthio, etc.),(13) —S(O)-aliphatic hydrocarbon group (for example, methylsulfinyl,ethylsulfinyl, propylsulfinyl, isopropylsulfinyl, butylsulfinyl,isobutylsulfinyl, tert-butylsulfinyl, pentylsulfinyl, hexylsulfinyl,heptylsulfinyl, octylsulfinyl, propenylsulfinyl, butenylsulfinyl,pentenylsulfinyl, hexenylsulfinyl, propynylsulfinyl, butynylsulfinyl,pentynylsulfinyl, hexynylsulfinyl, etc.),(14) —S(O)-cyclic group (for example, cyclopropylsulfinyl,cyclopentylsulfinyl, cyclohexylsulfinyl, phenylsulfinyl,naphthylsulfinyl, pyridinylsulfinyl, etc.),(15) —S(O)-aliphatic hydrocarbon-cyclic group (for example,cyclopentylmethylsulfinyl, cyclohexylmethylsulfinyl,phenylmethylsulfinyl, etc.),(16) —SO₂-aliphatic hydrocarbon group (for example, methylsulfonyl,ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl,isobutylsulfonyl, tert-butylsulfonyl, pentylsulfonyl, hexylsulfonyl,heptylsulfonyl, octylsulfonyl, propenylsulfonyl, butenylsulfonyl,pentenylsulfonyl, hexenylsulfonyl, propynylsulfonyl, butynylsulfonyl,pentynylsulfonyl, hexynylsulfonyl, etc.),(17) —SO₂-cyclic group (for example, cyclopropylsulfonyl,cyclopentylsulfonyl, cyclohexylsulfonyl, phenylsulfonyl,naphthylsulfonyl, pyridinylsulfonyl, etc.),(18) —SO₂-aliphatic hydrocarbon-cyclic group (for example,cyclopentylmethylsulfonyl, cyclohexylmethylsulfonyl,phenylmethylsulfonyl, etc.),(19) —O—CO-aliphatic hydrocarbon group (for example, methanoyloxy,ethanoyloxy, propanoyloxy, isopropanoyloxy, butanoyloxy, isobutanoyloxy,tert-butanoyloxy, pentanoyloxy, hexanoyloxy, heptanoyloxy, octanoyloxy,propenoyloxy, butenoyloxy, pentenoyloxy, hexenoyloxy, propynoyloxy,butynoyloxy, pentynoyloxy, hexynoyloxy, etc.),(20) —O—CO-cyclic group (for example, cyclopropylcarbonyloxy,cyclopentylcarbonyloxy, cyclohexylcarbonyloxy, phenylcarbonyloxy,naphthylcarbonyloxy, pyridinylcarbonyloxy, etc.),(21) —O—CO-aliphatic hydrocarbon-cyclic group (for example,cyclopentylmethanoyloxy, cyclohexylmethanoyloxy, phenylmethanoyloxy,etc.),(22) —CO-aliphatic hydrocarbon group (for example, methanoyl, ethanoyl,propanoyl, isopropanoyl, butanoyl, isobutanoyl, tert-butanoyl,pentanoyl, hexanoyl, heptanoyl, octanoyl, propenoyl, butenoyl,pentenoyl, hexenoyl, propynoyl, butynoyl, pentynoyl, hexynoyl, etc.),(23) —CO-cyclic group (for example, cyclopropylcarbonyl,cyclopentylcarbonyl, cyclohexylcarbonyl, phenylcarbonyl,naphthylcarbonyl, pyridinylcarbonyl, etc.),(24) —CO-aliphatic hydrocarbon-cyclic group (for example,cyclopentylmethanoyl, cyclohexylmethanoyl, phenylmethanoyl, etc.),(25) oxo group,(26) thioxo group,(27) sulfino group,(28) sulfo group,(29) amino group,(30) mono- or di-substituted amino group (“substituent” in “mono- ordi-substituted amino group” herein includes, for example, (1) aliphatichydrocarbon group, (2) cyclic group, and (3) aliphatic hydrocarbon groupsubstituted with a cyclic group, and examples thereof includemethylamino, ethylamino, propylamino, isopropylamino, butylamino,isobutylamino, tert-butylamino, pentylamino, hexylamino, heptylamino,octylamino, dimethylamino, diethylamino, dipropylamino, dibutylamino,dipentylamino, dihexylamino, diheptylamino, dioctylamino,N-methyl-N-ethylamino, cyclopropylamino, cyclopentylamino,cyclohexylamino, phenylamino, diphenylamino, dibenzylamino,N-phenyl-N-methylamino, N-phenyl-N-ethylamino, N-benzyl-N-methylamino,N-benzyl-N-ethylamino, N-cyclohexyl-N-propylamino, etc.),(31) sulfamoyl group,(32) mono- or di-substituted sulfamoyl group (“substituent” in “mono- ordi-substituted sulfamoyl group” include, for example, (1) aliphatichydrocarbon group, (2) cyclic group, and (3) aliphatic hydrocarbon groupsubstituted with a cyclic group, and examples thereof includeN-methylsulfamoyl, N-ethylsulfamoyl, N-propylsulfamoyl,N-isopropylsulfamoyl, N-butylsulfamoyl, N-isobutylsulfamoyl,N-(tert-butyl)sulfamoyl, N-pentylsulfamoyl, N-hexylsulfamoyl,N-heptylsulfamoyl, N-octylsulfamoyl, N,N-dimethylsulfamoyl,N,N-diethylsulfamoyl, N,N-dipropylsulfamoyl, N,N-dibutylsulfamoyl,N,N-dipentylsulfamoyl, N,N-dihexylsulfamoyl, N-methyl-N-ethylsulfamoyl,N-cyclopropylsulfamoyl, N-cyclopentylsulfamoyl, N-cyclohexylsulfamoyl,N-phenylsulfamoyl, N,N-diphenylsulfamoyl, N,N-dibenzylsulfamoyl,N-phenyl-N-methylsulfamoyl, N-phenyl-N-ethylsulfamoyl,N-benzyl-N-methylsulfamoyl, N-benzyl-N-ethylsulfamoyl,N-cyclohexyl-N-propylamino, etc.),(33) carboxy group,(34) —COO-aliphatic hydrocarbon group (for example, methoxycarbonyl,ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl,isobutoxycarbonyl, tert-butoxycarbonyl, pentoxycarbonyl,hexyloxycarbonyl, heptyloxycarbonyl, octyloxycarbonyl,propenyloxycarbonyl, butenyloxycarbonyl, pentenyloxycarbonyl,hexenyloxycarbonyl, propynyloxycarbonyl, butynyloxycarbonyl,pentynyloxycarbonyl, hexynyloxycarbonyl, etc.),(35) —COO-cyclic group (for example, cyclopropyloxycarbonyl,cyclopentyloxycarbonyl, cyclohexyloxycarbonyl, phenoxycarbonyl,naphthyloxycarbonyl, pyridinyloxycarbonyl, etc.),(36) —COO-aliphatic hydrocarbon-cyclic group (for example,cyclopentylmethoxycarbonyl, cyclohexylmethoxycarbonyl,phenylmethoxycarbonyl, etc.),(37) carbamoyl group,(38) mono- or di-substituted carbamoyl group (“substituent” in “mono- ordi-substituted carbamoyl group” herein includes, for example, (1)aliphatic hydrocarbon group, (2) cyclic group, and (3) aliphatichydrocarbon group substituted with a cyclic group, and examples thereofinclude N-methylcarbamoyl, N-ethylcarbamoyl, N-propylcarbamoyl,N-isopropylcarbamoyl, N-butylcarbamoyl, N-isobutylcarbamoyl,N-(tert-butyl)carbamoyl, N-pentylcarbamoyl, N-hexylcarbamoyl,N-heptylcarbamoyl, N-octylcarbamoyl, N-cyclopropylcarbamoyl,N-cyclopentylcarbamoyl, N-cyclohexylcarbamoyl, N-phenylcarbamoyl,N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N,N-dipropylcarbamoyl,N,N-dibutylcarbamoyl, N,N-dipentylcarbamoyl, N,N-dihexylcarbamoyl,N-methyl-N-ethylcarbamoyl, N,N-diphenylcarbamoyl, N,N-dibenzylcarbamoyl,N-phenyl-N-methylcarbamoyl, N-phenyl-N-ethylcarbamoyl,N-benzyl-N-methylcarbamoyl, N-benzyl-N-ethylcarbamoyl, etc.),(39) —NH—CO-aliphatic hydrocarbon group (for example, methanoylamino,ethanoylamino, propanoylamino, isopropanoylamino, butanoylamino,isobutanoylamino, tert-butanoylamino, pentanoylamino, hexanoylamino,heptanoylamino, octanoylamino, propenoylamino, butenoylamino,pentenoylamino, hexenoylamino, propynoylamino, butynoylamino,pentynoylamino, hexynoylamino, etc.),(40) —NH—CO-cyclic group (for example, cyclopropylcarbonylamino,cyclopentylcarbonylamino, cyclohexylcarbonylamino, phenylcarbonylamino,naphthylcarbonylamino, pyridinylcarbonylamino, etc.),(41) —NH—CO-aliphatic hydrocarbon-cyclic group (for example,cyclopentylmethanoylamino, cyclohexylmethanoylamino,phenylmethanoylamino, etc.),(42) —NH—SO₂-aliphatic hydrocarbon group (for example,methylsulfonylamino, ethylsulfonylamino, propylsulfonylamino,isopropylsulfonylamino, butylsulfonylamino, isobutylsulfonylamino,tert-butylsulfonylamino, pentylsulfonylamino, hexylsulfonylamino,heptylsulfonylamino, octylsulfonylamino, propenylsulfonylamino,butenylsulfonylamino, pentenylsulfonylamino, hexenylsulfonylamino,propynylsulfonylamino, butynylsulfonylamino, pentynylsulfonylamino,hexynylsulfonyl, etc.),(43) —NH—SO₂-cyclic group (for example, cyclopropylsulfonylamino,cyclopentylsulfonylamino, cyclohexylsulfonylamino, phenylsulfonylamino,naphthylsulfonylamino, pyridinylsulfonyl, etc.),(44) —NH—SO₂-aliphatic hydrocarbon-cyclic group (for example,cyclopentylmethylsulfonylamino, cyclohexylmethylsulfonylamino,phenylmethylsulfonyl, etc.),(45) cyano group,(46) hydrazino group,(47) nitro group,(48) nitroso group,(49) imino group,(50) mono-substituted imino group (“substituent” in the mono-substitutedimino group includes, for example, (1) aliphatic hydrocarbon group, (2)cyclic group, (3) aliphatic hydrocarbon group substituted with a cyclicgroup, (4) hydroxyl group, (5) —O-aliphatic hydrocarbon group, (6)—O-cyclic group, and (7) —O-aliphatic hydrocarbon-cyclic group, andexamples thereof include methylimino, ethylimino, propylimino,isopropylimino, butylimino, isobutylimino, (tert-butyl)imino,pentylimino, hexylimino, heptylimino, octylimino, cyclopropylimino,cyclopentylimino, cyclohexylimino, phenylimino, benzylimino,hydroxyimino, ethoxyimino, propoxyimino, isopropoxyimino, butoxyimino,cyclopentoxyimino, cyclohexyloxyimino, phenoxyimino, benzyloxyimino,etc.),(51) halogen atom (for example, fluorine atom, chlorine atom, bromineatom, iodine atom, etc.),(52) methyl group substituted with 1 to 3 halogen atom(s) (for example,fluoromethyl, difluoromethyl, trifluoromethyl, trichloromethyl, etc.),and(53) methoxy group substituted with 1 to 3 halogen atom(s) (for example,fluoromethoxy, difluoromethoxy, trifluoromethoxy, trichloromethoxy,etc.). These optional substituents may be substituted on the optionalsubstitutable position in optional substitutable number. The number ofsubstituents is preferably from 1 to 8, and more preferably from 1 to 5.The “aliphatic hydrocarbon group” and the “cyclic group” in T are asdefined above. Also, “-aliphatic hydrocarbon-” means a divalentaliphatic hydrocarbon group and includes, for example, a divalent groupin which one optional hydrogen atom is further removed from the“aliphatic hydrocarbon group”.

The “basic group” in the “group having a basic group” is notspecifically limited as long as it has a basic nitrogen atom. Examplesthereof include (a) amino group, (b) amidino group, (c) guanidino group,(d) hydrazino group, (e) mono- or di-substituted amino group, (f) mono-,di- or tri-substituted amidino group, (g) mono-, di-, tri- ortetra-substituted guanidino group, (h) mono-, di- or tri-substitutedhydrazino group, and (i) nitrogen-containing heterocyclic ring which mayhave a substituent(s). Examples of the “substituent” in the “mono- ordi-substituted amino group” herein include (1) cyclic group substitutedwith a substituent(s) (substituent includes those exemplified as for theabove-described T and cyclic group is as defined above), (2) aliphatichydrocarbon group substituted with a substituent(s) (substituentincludes those exemplified as for the above-described T and aliphatichydrocarbon is as defined above), (3) aliphatic hydrocarbon groupsubstituted with a cyclic group substituted with a substituent(s)(substituent includes those exemplified as for the above-described T andaliphatic hydrocarbon and cyclic groups are as defined above), and (4)substituents exemplified as for the above-described T. These optionalsubstituents may be substituted on the optional substitutable positionin optional substitutable number. The number of substituents ispreferably from 1 to 8, and more preferably from 1 to 5. Examplesthereof include methylamino, ethylamino, propylamino, isopropylamino,butylamino, isobutylamino, tert-butylamino, pentylamino, hexylamino,heptylamino, octylamino, dimethylamino, diethylamino, dipropylamino,dibutylamino, dipentylamino, dihexylamino, diheptylamino, dioctylamino,N-methyl-N-ethylamino, cyclopropylamino, cyclopentylamino,cyclohexylamino, phenylamino, diphenylamino, dibenzylamino,N-phenyl-N-methylamino, N-phenyl-N-ethylamino, N-benzyl-N-methylamino,N-benzyl-N-ethylamino, N-benzyl-N-cyclohexylamino,N-cyclohexyl-N-propylamino, N-cyclohexyl-N-(3-hydroxypropyl)amino,N-(4-hydroxycyclohexyl)-N-propylamino,N-(4-hydroxycyclohexyl)-N-(3-hydroxypropyl)amino,N-(4-hydroxycyclohexyl)methyl-N-propylamino, N-cyclohexyl-N-acetylamino,N-(3-methoxypropyl)-N-propylamino, N-(2-carboxyethyl)-N-propylamino,N-(2-ethylpropyl)-N-propylamino, N-cyclohexyl-N-(methylsulfonyl)amino,N-(tetrahydropyran-4-yl)-N-propylamino, andN-(indan-2-yl)-N-propylamino.

Examples of the “substituent” in the “mono-, di- or tri-substitutedamidino group” include (1) aliphatic hydrocarbon group (which is asdefined above), (2) cyclic group (which is as defined above), (3)aliphatic hydrocarbon group substituted with a cyclic group (aliphatichydrocarbon and cyclic groups are as defined above). Examples of the“mono-, di- or tri-substituted amidino group” include methylamidino,ethylamidino, propylamidino, isopropylamidino, butylamidino,isobutylamidino, tert-butylamidino, pentylamidino, hexylamidino,heptylamidino, octylamidino, N,N-dimethylamidino, N,N′-dimethylamidino,N,N,N′-trimethylamidino, N,N-diethylamidino, N,N′-diethylamidino,N,N,N′-triethylamidino, N,N-dipropylamidino, N,N′-dipropylamidino,N,N,N′-tripropylamidino, N,N-dibutylamidino, N,N′-dibutylamidino,N,N,N′-tributylamidino, N,N-dipentylamidino, N,N′-dipentylamidino,N,N,N′-tripentylamidino, N,N-dihexylamidino, N,N′-dihexylamidino,N,N,N′-trihexylamidino, N,N-diheptylamidino, N,N′-diheptylamidino,N,N,N′-triheptylamidino, N,N-dioctylamidino, N,N′-dioctylamidino,N,N,N′-trioctylamidino, N-methyl-N-ethylamidino,N-methyl-N′-ethylamidino, cyclopropylamidino, cyclopentylamidino,cyclohexylamidino, phenylamidino, N,N-diphenylamidino,N,N′-diphenylamidino, N,N,N′-triphenylamidino, N,N-dibenzylamidino,N,N′-dibenzylamidino, N,N,N′-tribenzylamidino,N-phenyl-N′-methylamidino, N-phenyl-N′-ethylamidino,N-benzyl-N-methylamidino, and N-benzyl-N-ethylamidino.

Examples of the “substituent” in the “mono-, di-, tri- ortetra-substituted guanidino group” include (1) aliphatic hydrocarbongroup (which is as defined above), (2) cyclic group (which is as definedabove), and (3) aliphatic hydrocarbon group substituted with a cyclicgroup (aliphatic hydrocarbon and cyclic groups are as defined above).Examples of the “mono-, di-, tri- or tetra-substituted guanidino group”include, for example, methylguanidino, ethylguanidino, propylguanidino,isopropylguanidino, butylguanidino, isobutylguanidino,tert-butylguanidino, pentylguanidino, hexylguanidino, heptylguanidino,octylguanidino, N,N-dimethylguanidino, N,N′-dimethylguanidino,N,N,N′-trimethylguanidino, N,N,N′,N″-tetramethylguanidino,N,N-diethylguanidino, N,N′-diethylguanidino, N,N,N′-triethylguanidino,N,N,N′,N″-tetraethylguanidino, N,N-dipropylguanidino,N,N′-dipropylguanidino, N,N,N′-tripropylguanidino,N,N,N′,N″-tetrapropylguanidino, N,N-dibutylguanidino,N,N′-dibutylguanidino, N,N,N′-tributylguanidino,N,N,N′,N″-tetrabutylguanidino, N,N-dipentylguanidino,N,N′-dipentylguanidino, N,N,N′-tripentylguanidino,N,N,N′,N″-tetrapentylguanidino, N,N-dihexylguanidino,N,N′-dihexylguanidino, N,N,N′-trihexylguanidino,N,N,N′,N″-tetrahexylguanidino, N,N-diheptylguanidino,N,N′-diheptylguanidino, N,N,N′-triheptylguanidino,N,N,N′,N″-tetraheptylguanidino, N,N-dioctylguanidino,N,N′-dioctylguanidino, N,N,N′-trioctylguanidino,N,N,N′,N″-tetraoctylguanidino, N-methyl-N-ethylguanidino,N-methyl-N′-ethylguanidino, cyclopropylguanidino, cyclopentylguanidino,cyclohexylguanidino, phenylguanidino, N,N-diphenylguanidino,N,N′-diphenylguanidino, N,N,N′-triphenylguanidino,N,N,N′,N″-tetraphenylguanidino, N,N-dibenzylguanidino,N,N′-dibenzylguanidino, N,N,N′-tribenzylguanidino,N,N,N′,N″-tetrabenzylguanidino, N-phenyl-N′-methylguanidino,N-phenyl-N′-ethylguanidino, N-benzyl-N-methylguanidino, andN-benzyl-N-ethylguanidino.

Examples of the “substituent” in the “mono-, di- or tri-substitutedhydrazino group” include (1) aliphatic hydrocarbon group (which is asdefined above), (2) cyclic group (which is as defined above), and (3)aliphatic hydrocarbon group substituted with a cyclic group (aliphatichydrocarbon and cyclic groups are as defined above). Examples of the“mono-, di- or tri-substituted hydrazino group” include, for example,methylhydrazino, ethylhydrazino, propylhydrazino, isopropylhydrazino,butylhydrazino, isobutylhydrazino, tert-butylhydrazino, pentylhydrazino,hexylhydrazino, heptylhydrazino, octylhydrazino, N,N-dimethylhydrazino,N,N′-dimethylhydrazino, N,N,N′-trimethylhydrazino, N,N-diethylhydrazino,N,N′-diethylhydrazino, N,N,N′-triethylhydrazino, N,N-dipropylhydrazino,N,N′-dipropylhydrazino, N,N,N′-tripropylhydrazino, N,N-dibutylhydrazino,N,N′-dibutylhydrazino, N,N,N′-tributylhydrazino, N,N-dipentylhydrazino,N,N′-dipentylhydrazino, N,N,N′-tripentylhydrazino, N,N-dihexylhydrazino,N,N′-dihexylhydrazino, N,N,N′-trihexylhydrazino, N,N-diheptylhydrazino,N,N′-diheptylhydrazino, N,N,N′-triheptylhydrazino, N,N-dioctylhydrazino,N,N′-dioctylhydrazino, N,N,N′-trioctylhydrazino,N-methyl-N-ethylhydrazino, N-methyl-N′-ethylhydrazino,cyclopropylhydrazino, cyclopentylhydrazino, cyclohexylhydrazino,phenylhydrazino, N,N-diphenylhydrazino, N,N′-diphenylhydrazino,N,N,N′-triphenylhydrazino, N,N-dibenzylhydrazino,N,N′-dibenzylhydrazino, N,N,N′-tribenzylhydrazino,N-phenyl-N′-methylhydrazino, N-phenyl-N′-ethylhydrazino,N-benzyl-N-methylhydrazino, and N-benzyl-N-ethylhydrazino.

The “nitrogen-containing heterocyclic ring” in the “nitrogen-containingheterocyclic ring which may have a substituent(s)” include, for example,a heterocyclic ring which is a 3- to 11-membered monocyclic or bicyclicheterocyclic ring having, as a heteroatom, at least one nitrogen atom,and also may have an oxygen atom(s) and/or an optionally oxidized sulfuratom(s) and has basicity and the like. Example of the “heterocyclic ringwhich is a 3- to 11-membered monocyclic or bicyclic heterocyclic ringhaving, as a heteroatom, at least one nitrogen atom, and also may havean oxygen atom(s) and/or an optionally oxidized sulfur atom(s) and hasbasicity” herein, include pyrrole, imidazole, triazole, pyrazole,pyridine, pyrazine, pyrimidine, pyridazine, azepine, diazepine, oxazole,thiazole, isoxazole, isothiazole, indole, isoindole, quinoline,isoquinoline, benzoxazole, benzothiazole, benzimidazole, aziridine,azetidine, pyrrolidine, piperidine, piperazine, morpholine,thiomorpholine, perhydroazepine, perhydrodiazepine, indoline,isoindoline, quinazoline, tetrahydroquinoline, perhydroquinoline,tetrahydroisoquinoline, perhydroisoquinoline, tetrahydronaphthyridine,quinoxaline, tetrahydroquinoxaline, dihydrobenzimidazole,perhydrobenzimidazole, carbazole, tetrahydrocarbazole,azabicyclo[3.2.1]octane, quinuclidine, 2,8-diazaspiro[4.5]decane,1,4,9-triazaspiro[5.5]undecane, 3,9-diazaspiro[5.5]undecane,2,9-diazaspiro[5.5]undecane, 1,6-diazaspiro[3.4]octane,1,5-diazaspiro[3.4]octane, 1,7-diazaspiro[3.5]nonane,1,6-diazaspiro[3.5]nonane, 1,5-diazaspiro[3.5]nonane,1,7-diazaspiro[4.4]nonane, 1,6-diazaspiro[4.4]nonane,1,8-diazaspiro[4.5]decane, 1,7-diazaspiro[4.5]decane,2,6-diazaspiro[3.4]octane, 1,6-diazaspiro[4.5]decane,2,6-diazaspiro[3.5]nonane, 1,9-diazaspiro[5.5]undecane,1,8-diazaspiro[5.5]undecane, 6-azaspiro[3.5]nonane,6-azaspiro[3.4]octane, 2-azaspiro[3.4]octane,1,7-diazaspiro[5.5]undecane, 1,4,9-triazaspiro[5.5]undecane,1,3,8-triazaspiro[4.5]decane, 1-thia-4,9-diazaspiro[5.5]undecane, and1-thia-4,8-diazaspiro[5.5]undecane ring.

The “substituent” in the “nitrogen-containing heterocyclic ring whichmay have a substituent(s)” includes those exemplified as for theabove-described T. These optional substituents may be substituted on theoptional substitutable position in optional substitutable number. Thenumber of substituents is preferably from 1 to 8, and more preferablyfrom 1 to 5.

In the present specification, examples of the “substituent” of the “animidazole ring which may have a substituent(s), a benzoimidazole ringwhich may have a substituent(s), or a pyridine ring which may have asubstituent(s)” represented by ring A^(1A) and ring A^(2A) include thoseexemplified as for the above-described T and these optional substituentsmay be substituted on the substitutable position and the number ofsubstituents is from 1 to 5, and preferably from 1 to 2.

In the present specification, “spacer having a main chain of 1 to 4atom(s)” represented by B¹ and B², and “spacer having a main chain of 1to 4 atom(s)” represented by L mean the space wherein 1 to 4 atom(s) ofthe main chain are arranged in a line. The “number of atoms of mainchain” is counted so that the number of atoms of the main chain isminimized. For example, it is counted that the number of atoms of1,2-cyclopentylene is 2 and the number of atoms of 1,3-cyclopentylene is3. Examples of the “spacer having a main chain of 1 to 4 atom(s)”include divalent group composed of 1 to 4 groups selected optionallyfrom —O—, —S—, —CO—, —SO—, —SO₂—, divalent nitrogen atom which may havea substituent, divalent aliphatic hydrocarbon group having 1 to 4 carbonatom(s) which may have a substituent(s), and divalent 3- to 8-memberedmonocyclic cyclic group which may have a substituent(s), wherein 1 to 4atom(s) of the main chain are arranged in a line.

The “divalent nitrogen atom which may have a substituent” represents, inaddition to —NH—, those wherein hydrogen atom in the “—NH-” group areoptionally substituted with (1) aliphatic hydrocarbon group, (2) cyclicgroup, (3) aliphatic hydrocarbon group substituted with a cyclic group,(4) hydroxyl group, (5) —O-aliphatic hydrocarbon group, (6) —O-cyclicgroup, (7) —O-aliphatic hydrocarbon-cyclic group, (8) —SO₂-aliphatichydrocarbon group, (9) —SO₂-cyclic group, (10) —SO₂-aliphatichydrocarbon-cyclic group, (11) —CO-aliphatic hydrocarbon, (12)—CO-cyclic group, (13) —CO-aliphatic hydrocarbon-cyclic group, (14)carboxy group, (15) —COO-aliphatic hydrocarbon, (16) —COO-cyclic group,or (17) —COO-aliphatic hydrocarbon-cyclic group, among the substituentsexemplified as for the above-described T.

Examples of the “divalent aliphatic hydrocarbon group having 1 to 4carbon atom(s)” in the “divalent aliphatic hydrocarbon group having 1 to4 carbon atom(s) which may have a substituent(s)” include C1-4 alkylenegroup (for example, —CH₂—, —(CH₂)₂—, —(CH₂)₃—, —(CH₂)₄—, etc.), C2-4alkenylene group (for example, —CH═CH—, —CH₂—CH═CH—, —CH═CH—CH₂—,—(CH₂)₂—CH═CH—, —CH═CH—(CH₂)₂—, —CH₂—CH═CH—CH₂—, etc.), and C2-4alkynylene group (for example, —C≡C—, —CH₂—C≡C—, —C≡C—CH₂—,—(CH₂)₂—C≡C—, —C≡C—(CH₂)₂—, —CH₂—C≡C—CH₂—, etc.). Examples of the“substituent” in the “divalent aliphatic hydrocarbon group having 1 to 4carbon atom(s) which may have a substituent(s)” include thoseexemplified as for the above-described T, and these optionalsubstituents may be substituted on the substitutable position and thenumber of substituents is from 1 to 5, and preferably from 1 to 2.

Examples of the “divalent 3- to 8-membered monocyclic cyclic group” inthe “divalent 3- to 8-membered monocyclic cyclic group which may have asubstituent(s)” include divalent group which can be obtained byeliminating optional two hydrogen atoms from the “C3-8 monocyclic cyclicgroup”. Examples of the “C3-8 monocyclic cyclic group” herein include“C3-8 monocyclic carbocyclic ring” and “3- to 8-membered monocyclicheterocyclic ring”. The “C3-8 monocyclic carbocyclic ring” includes C3-8monocyclic unsaturated carbocyclic ring, and partially or completelysaturated one thereof. Examples of the “C3-8 monocyclic unsaturatedcarbocyclic ring, and partially or completely saturated one thereof”include cyclopropane, cyclobutane, cyclopentane, cyclohexane,cycloheptane, cyclooctane, cyclopentene, cyclohexene, cycloheptene,cyclooctene, cyclopentadiene, cyclohexadiene, cycloheptadiene,cyclooctadiene, and benzene rings. Among these, the “C3-8 monocyclicaromatic carbocyclic ring” includes, for example, benzene ring.

Examples of the “3- to 8-membered monocyclic heterocyclic ring” include“3- to 8-membered monocyclic heterocyclic ring having, as a heteroatom,1 to 4 nitrogen atom(s), 1 to 2 oxygen atom(s) and/or 1 to 2 sulfuratom(s)”. The “3- to 8-membered monocyclic heterocyclic ring having, asa heteroatom, 1 to 4 nitrogen atom(s), 1 to 2 oxygen atom(s) and/or 1 to2 sulfur atom(s)” herein includes 3- to 8-membered monocyclicunsaturated heterocyclic ring having, as a heteroatom, 1 to 4 nitrogenatom(s), 1 to 2 oxygen atom(s) and/or 1 to 2 sulfur atom(s), andpartially or completely saturated one thereof. Examples of the “3- to8-membered monocyclic unsaturated heterocyclic ring having, as aheteroatom, 1 to 4 nitrogen atom(s), 1 to 2 oxygen atom(s) and/or 1 to 2sulfur atom(s), and partially or completely saturated one thereof”include pyrrole, imidazole, triazole, tetrazole, pyrazole, pyridine,pyrazine, pyrimidine, pyridazine, azepine, diazepine, furan, pyran,oxepine, thiophene, thiopyran, thiepine, oxazole, isoxazole, thiazole,isothiazole, furazan, oxadiazole, oxazine, oxadiazine, oxazepine,oxadiazepine, thiadiazole, thiazine, thiadiazine, thiazepine,thiadiazepine, aziridine, azetidine, pyrroline, pyrrolidine,imidazoline, imidazolidine, triazoline, triazolysine, tetrazoline,tetrazolidine, pyrazoline, pyrazolidine, dihydropyridine,tetrahydropyridine, piperidine, dihydropyrazine, tetrahydropyrazine,piperazine, dihydropyrimidine, tetrahydropyrimidine, perhydropyrimidine,dihydropyridazine, tetrahydropyridazine, perhydropyridazine,dihydroazepine, tetrahydroazepine, perhydroazepine, dihydrodiazepine,tetrahydrodiazepine, perhydrodiazepine, oxirane, oxetane, dihydrofuran,tetrahydrofuran, dihydropyran, tetrahydropyran, dihydrooxepine,tetrahydrooxepine, perhydrooxepine, thiirane, thietane,dihydrothiophene, tetrahydrothiophene, dihydrothiopyran,tetrahydrothiopyran, dihydrothiepine, tetrahydrothiepine,perhydrothiepine, dihydrooxazole, tetrahydrooxazole (oxazolidine),dihydroisoxazole, tetrahydroisoxazole (isoxazolidine), dihydrothiazole,tetrahydrothiazole (thiazolidine), dihydroisothiazole,tetrahydroisothiazole (isothiazolidine), dihydrofurazan,tetrahydrofurazan, dihydrooxadiazole, tetrahydrooxadiazole(oxadiazolidine), dihydrooxazine, tetrahydrooxazine, dihydrooxadiazine,tetrahydrooxadiazine, dihydrooxazepine, tetrahydrooxazepine,perhydrooxazepine, dihydrooxadiazepine, tetrahydrooxadiazepine,perhydrooxadiazepine, dihydrothiadiazole, tetrahydrothiadiazole(thiadiazolidine), dihydrothiazine, tetrahydrothiazine,dihydrothiadiazine, tetrahydrothiadiazine, dihydrothiazepine,tetrahydrothiazepine, perhydrothiazepine, dihydrothiadiazepine,tetrahydrothiadiazepine, perhydrothiadiazepine, morpholine,thiomorpholine, oxathiane, dioxolane, dioxane, dithiolane, dithianerings and the like. Among these, examples of the “3- to 8-memberedmonocyclic aromatic heterocyclic ring having, as a heteroatom, 1 to 4nitrogen atom(s), 1 to 2 oxygen atom(s) and/or 1 to 2 sulfur atom(s)”include pyrrole, imidazole, triazole, tetrazole, pyrazole, pyridine,pyrazine, pyrimidine, pyridazine, furan, thiophene, oxazole, isoxazole,thiazole, isothiazole, furazan, oxadiazole, thiadiazole rings and thelike. Examples of the “substituent” in the “divalent 3- to 8-memberedmonocyclic cyclic group which may have a substituent(s)” include (1)aliphatic hydrocarbon group substituted with a substituent(s) (asubstituent herein includes those exemplified as for T), (2) cyclicgroup substituted with a substituent(s) (a substituent herein includesthose exemplified as for T), and (3) substituents exemplified as for T,and the like, and these optional substituents may be substituted on thesubstitutable position and the number of substituents is from 1 to 8,and preferably from 1 to 5.

In the present specification, the “spacer having a main chain of 1 to 10atom(s)” represented by E means the space wherein 1 to 10 atom(s) of themain chain are arranged in a line. The “number of atoms of main chain”is counted so that the number of atoms of the main chain is minimized.For example, it is counted that the number of

atoms of is 4, the number of atoms of

is 6 and the number of atoms of

is 6. Examples of the “spacer having a main chain of 1 to 10 atom(s)”include divalent group composed of 1 to 10 groups selected optionallyfrom —O—, —S—, —CO—, —SO—, —SO₂—, divalent nitrogen atom which may havea substituent, divalent aliphatic hydrocarbon group having 1 to 10carbon atom(s) which may have a substituent(s), and divalent 3- to15-membered monocyclic cyclic group which may have a substituent(s),wherein 1 to 10 atom(s) of the main chain are arranged in a line. The“divalent nitrogen atom which may have a substituent” is as definedabove. Examples of the “divalent aliphatic hydrocarbon group having 1 to10 carbon atom(s)” in the “divalent aliphatic hydrocarbon group having 1to 10 carbon atom(s) which may have a substituent(s)” include C1-10alkylene group (methylene, ethylene, trimethylene, tetramethylene,pentamethylene, hexamethylene, heptamethylene, octamethylene,nonamethylene, decamethylene group, and isomers thereof), C2-10alkenylene group (ethenylene, propenylene, butenylene, pentenylene,hexenylene, heptenylene, octenylene, nonenylene, decenylene group, andisomers thereof), and C2-10 alkynylene group (ethynylene, propynylene,butynylene, pentynylene, hexynylene, heptynylene, octynylene,nonynylene, decynylene group, and isomers thereof). Also, examples ofthe “substituent” in the “optionally substituted divalent aliphatichydrocarbon group having 1 to 10 carbon atom(s)” include (1) analiphatic hydrocarbon group which is substituted with a substituent(wherein a substituent includes those exemplified as for T), (2) cyclicgroup substituted with a substituent(s) (wherein a substituent includesthose exemplified as for T), and (3) substituents exemplified as for T,and these optional substituents may be substituted on the substitutableposition and the number of substituents is from 1 to 5, and preferablyfrom 1 to 2. The “divalent 3- to 15-membered cyclic group” in the“divalent 3- to 15-membered cyclic group which may have asubstituent(s)” includes, for example, a divalent group which can beobtained by removing two optional hydrogen atoms from the “3- to15-membered cyclic group”. Examples of the “3- to 15-membered cyclicgroup” here include the C3-15 monocyclic or condensed carbocyclic ringdefined above, a C4-15 bridged polycyclic carbocyclic ring, or a C7-15spiro-bound polycyclic carbocyclic ring, or a 3- to 15-memberedmonocyclic or condensed heterocyclic ring having, as a heteroatom, 1 to4 nitrogen atom(s), 1 to 2 oxygen atom(s) and/or 1 to 2 sulfur atom(s),4- to 15-membered bridged polycyclic heterocyclic ring having, as aheteroatom, 1 to 4 nitrogen atom(s), 1 to 2 oxygen atom(s) and/or 1 to 2sulfur atom(s), and a 7- to 15-membered spiro-bound polycyclicheterocyclic ring having, as a heteroatom, 1 to 4 nitrogen atom(s), 1 to2 oxygen atom(s) and/or 1 to 2 sulfur atom(s). The “substituent” in the“divalent 3- to 15-membered cyclic group which may have asubstituent(s)” includes, for example, substituents exemplified as forT, and these optional substituents may be substituted on thesubstitutable position and the number of substituents is from 1 to 5,and preferably from 1 to 2.

In the present specification, the “3- to 8-membered monocyclic groupwhich may have a substituent(s)” represented by the ring E¹ has the samemeaning as defined in B¹.

In the present specification, examples of the “substituent” in the“benzene ring which may have a substituent(s), cyclohexane ring whichmay have a substituent(s), cyclopentane ring which may have asubstituent(s), pyrrolidine ring which may have a substituent(s), orpiperidine ring which may have a substituent(s)” represented by the ringE² include an aliphatic hydrocarbon group which may have asubstituent(s), a —CO-aliphatic hydrocarbon group, carboxyl group, and a—COO-aliphatic hydrocarbon group. Examples of the “substituent” in the“aliphatic hydrocarbon group which may have a substituent(s)” hereinclude a —CO-aliphatic hydrocarbon group, a carboxyl group, and a—COO-aliphatic hydrocarbon group.

In the present specification, “-(nitrogen atom which may have asubstituent)-” in “-(aliphatic hydrocarbon having 1 to 3 carbon atom(s)which may have a substituent(s))-(nitrogen atom which may have asubstituent)-” represented by L^(A) has the same meaning as in the“divalent nitrogen atom which may have a substituent”. Examples of the“aliphatic hydrocarbon having 1 to 3 carbon atom(s)” in the “aliphatichydrocarbon having 1 to 3 carbon atom(s) which may have asubstituent(s)” include C1 to 3 alkylene group (for example, methylene,ethylene, trimethylene, etc.), C2-3 alkenylene group (for example,ethenylene, propenylene, etc.), and C2-3 alkynylene group (for example,ethynylene, propynylene, etc.). Examples of the “substituent” in the“aliphatic hydrocarbon having 1 to 3 carbon atom(s) which may have asubstituent(s)” include those exemplified as for T, and these optionalsubstituents may be substituted on the substitutable position and thenumber of substituents is from 1 to 3.

In the present specification, the “divalent aliphatic hydrocarbon grouphaving 1 to 4 carbon atom(s) which may have a substituent(s)”represented by L_(A) is as defined above.

In the present specification, examples of “aliphatic hydrocarbon groupwhich is substituted with a group having a basic group, and also mayhave a substituent(s)” represented by J include (1) an aliphatichydrocarbon group which is substituted with a basic group, and also mayhave a substituent(s), (2) an aliphatic hydrocarbon group which issubstituted with a cyclic group substituted with a basic group, and alsomay have a substituent(s), and (3) an aliphatic hydrocarbon group whichis substituted with an aliphatic hydrocarbon group substituted with abasic group, and also may have a substituent(s). Also, examples of“monocyclic or condensed cyclic group which is substituted with a grouphaving a basic group, and also may have a substituent(s)” represented byJ include (1) a monocyclic or condensed cyclic group which issubstituted with a basic group, and also may have a substituent(s), (2)a monocyclic or condensed cyclic group which is substituted with acyclic group substituted with a basic group, and also may have asubstituent(s), and (3) a monocyclic or condensed cyclic group which issubstituted with an aliphatic hydrocarbon group substituted with a basicgroup, and also may have a substituent(s). Examples of “spiro-boundcyclic group which may be substituted with a group having a basic group,and also may have a substituent(s)” represented by J include (1) aspiro-bound cyclic group which may be substituted with a basic group,and also may have a substituent(s), (2) a spiro-bound cyclic group whichmay be substituted with a cyclic group substituted with a basic group,and also may have a substituent(s), and (3) a spiro-bound cyclic groupwhich may be substituted with an aliphatic hydrocarbon group substitutedwith a basic group, and also may have a substituent(s). Also, examplesof “bridged cyclic group which may be substituted with a group having abasic group, and also may have a substituent(s)” represented by Jinclude (1) a bridged cyclic group which may be substituted with a basicgroup, and also may have a substituent(s), (2) a bridged cyclic groupwhich may be substituted with a cyclic group substituted with a basicgroup, and also may have a substituent(s), and (3) a bridged cyclicgroup which may be substituted with an aliphatic hydrocarbon groupsubstituted with a basic group, and also may have a substituent(s).Herein, the “monocyclic or condensed cyclic group” in the “monocyclic orcondensed cyclic group which is substituted with a group having a basicgroup, and also may have a substituent(s)” has the same meaning as inthe “monocyclic or condensed cyclic group in the “cyclic group”. The“spiro-bound cyclic group” in the “spiro-bound cyclic group which may besubstituted with a group having a basic group, and also may have asubstituent(s)” has the same meaning as in the “spiro-bound polycycliccyclic group” in the “cyclic group”. The “bridged cyclic group” of the“bridged cyclic group which may be substituted with a group having abasic group, and also may have a substituent(s)” has the same meaning asin the “bridged polycyclic cyclic group” in the “cyclic group”.

In the present specification, the “spiro-bound polycyclic heterocyclicring or bridged polycyclic heterocyclic ring which has at least onenitrogen atom, and also may have an oxygen atom(s) and/or an optionallyoxidized sulfur atom(s)” in the “spiro-bound polycyclic heterocyclicring or bridged polycyclic heterocyclic ring which has at least onenitrogen atom and also may have an oxygen atom(s) and/or an optionallyoxidized sulfur atom(s), and which may be substituted with a grouphaving a basic group and also may have a substituent(s)” represented byJ includes spiro-bound polycyclic heterocyclic ring which has at leastone nitrogen atom, and also may have an oxygen atom(s) and/or anoptionally oxidized sulfur atom(s), and bridged polycyclic heterocyclicring which has at least one nitrogen atom, and also may have an oxygenatom(s) and/or an optionally oxidized sulfur atom(s). Examples of the“spiro-bound polycyclic heterocyclic ring which has at least onenitrogen atom, and also may have an oxygen atom(s) and/or an optionallyoxidized sulfur atom(s)” include, for example, azaspiro[4.4]nonane,oxazaspiro[4.4]nonane, azaspiro[4.5]decane, oxazaspiro[4.5]decane,azaspiro[5.5]undecane, 2,7-diazaspiro[3.5]nonane,2,8-diazaspiro[4.5]decane,2,7-diazaspiro[4.5]decane-2,9-diazaspiro[5.5]undecane,2,8-diazaspiro[5.5]undecane, 3,9-diazaspiro[5.5]undecane,2,7-diazaspiro[4.4]nonane, 1,2-dihydrospiro[indole-3,4′-piperidine],2,3-dihydro-1H-spiro[isoquinoline-4,4′-piperidine],1′,4′-dihydro-2′H-spiro[piperidine-4,3′-quinoline],2′,3′-dihydro-1′H-spiro[piperidine-4,4′-quinoline],8-azaspiro[4.5]decane, 8-azaspiro[4.5]decane, 7-azaspiro[4.5]decane,3-azaspiro[5.5]undecane, 2-azaspiro[5.5]undecane,1-oxa-4,8-diazaspiro[5.5]undecane, 1-oxa-4,9-diazaspiro[5.5]undecane,3,4-dihydrospiro[chromene-2,4′-piperidine], 2-azaspiro[4.4]nonane,7-azaspiro[3.5]nonane, 2,3-dihydrospiro[indene-1,4′-piperidine],3,4-dihydro-2H-spiro[naphthalene-1,4′-piperidine],3,4-dihydro-1H-spiro[naphthalene-2,4′-piperidine],2-azaspiro[4.5]decane, 2-azaspiro[3.5]nonane,1′,2′-dihydrospiro[cyclohexane-1,3′-indole],2′,3′-dihydro-1′H-spiro[cyclohexane-1,4′-isoquinoline],1′,4′-dihydro-2′H-spiro[cyclohexane-1,3′-quinoline],1,6-diazaspiro[3.4]octane, 1,5-diazaspiro[3.4]octane,1,7-diazaspiro[3.5]nonane, 1,6-diazaspiro[3.5]nonane,1,5-diazaspiro[3.5]nonane, 1,7-diazaspiro[4.4]nonane,1,6-diazaspiro[4.4]nonane, 1,8-diazaspiro[4.5]decane,1,7-diazaspiro[4.5]decane, 2,6-diazaspiro[3.4]octane,1,6-diazaspiro[4.5]decane, 2,6-diazaspiro[3.5]nonane,1,9-diazaspiro[5.5]undecane, 1,8-diazaspiro[5.5]undecane,6-azaspiro[3.5]nonane, 6-azaspiro[3.4]octane, 2-azaspiro[3.4]octane,1,7-diazaspiro[5.5]undecane, 1,4,9-triazaspiro[5.5]undecane,1,3,8-triazaspiro[4.5]decane, 1-thia-4,9-diazaspiro[5.5]undecane,1-thia-4,8-diazaspiro[5.5]undecane and the like. Examples of the“bridged polycyclic heterocyclic ring which has at least one nitrogenatom, and also may have an oxygen atom(s) and/or an optionally oxidizedsulfur atom(s)” include, for example, azabicyclo[2.2.1]heptane,azabicyclo[3.1.1]heptane, azabicyclo[3.2.1]octane,azabicyclo[2.2.2]octane, diazabicyclo[2.2.2]octane,1-azatricyclo[3.3.1.1^(3,7)]decane, 3-azabicyclo[3.3.1]nonane,3,7-diazabicyclo[3.3.1]nonane and the like.

In the present specification, the “7- to 15-membered bicyclicspiro-bound heterocyclic ring wherein a ring comprising the spiro-boundheterocyclic ring is a monocyclic ring composed of at least one nitrogenatom and carbon atoms, and/or a monocyclic ring composed of at least onenitrogen atom, one oxygen atom and carbon atoms” represented by Jincludes (1) 7- to 15-membered bicyclic spiro-bound heterocyclic ringwhich consists of two spiro-bound (a) 4- to 8-membered monocyclic ringscomposed of at least one nitrogen atom and carbon atoms, (2) 7- to15-membered bicyclic spiro-bound heterocyclic ring which consists ofspiro-bound (a) 4- to 8-membered monocyclic ring composed of at leastone nitrogen atom and carbon atoms, and (b) 4- to 8-membered monocyclicring composed of at least one nitrogen atom, one oxygen atom and carbonatoms, and (3) 7- to 15-membered bicyclic spiro-bound heterocyclic ringwhich consists of two spiro-bound (b) monocyclic rings composed of atleast one nitrogen atom, one oxygen atom and carbon atoms

“(1) 7- to 15-membered bicyclic spiro-bound heterocyclic ring whichconsists of two spiro-bound (a) 4- to 8-membered monocyclic ringscomposed of at least one nitrogen atom and carbon atoms” means that tworings selected optionally from “(a) 4- to 8-membered monocyclic ringcomposed of at least one nitrogen atom and carbon atoms” share onecarbon atom. The shared carbon atom may be any carbon atom as long as itis a carbon atom constituting the monocyclic ring.

“(2) 7- to 15-membered bicyclic spiro-bound heterocyclic ring whichconsists of spiro-bound (a) 4- to 8-membered monocyclic ring composed ofat least one nitrogen atom and carbon atoms, and (b) 4- to 8-memberedmonocyclic ring composed of at least one nitrogen atom, one oxygen atomand carbon atoms” means that one ring selected optionally from “(a) 4-to 8-membered monocyclic ring composed of at least one nitrogen atom andcarbon atoms” and one ring selected optionally from “(b) 4- to8-membered monocyclic ring composed of at least one nitrogen atom, oneoxygen atom and carbon atoms” share one carbon atom. The shared carbonatom may be any carbon atom as long as it is a carbon atom constitutingthe monocyclic ring.

“(3) 7- to 15-membered bicyclic spiro-bound heterocyclic ring whichconsists of two spiro-bound (b) monocyclic rings composed of at leastone nitrogen atom, one oxygen atom and carbon atoms” means that tworings selected optionally from “(b) monocyclic ring composed of at leastone nitrogen atom, one oxygen atom and carbon atoms” shares one carbonatom. The shared carbon atom may be any carbon atom as long as it is acarbon atom constituting the monocyclic ring.

In addition, examples of the “4- to 8-membered monocyclic ring composedof at least one nitrogen atom and carbon atoms” include, for example,azetidine, pyrrolidine, piperidine, piperazine, azepane, 1,4-diazepane,azocane, 1,4-diazocane, 1,5-diazocane, and the like.

Examples of the “4- to 8-membered monocyclic ring composed of at leastone nitrogen atom, one oxygen atom and carbon atoms” include, forexample, 1,4-oxazepane, 1,4-oxazocane, 1,5-oxazocane and the like.

Examples of the “(1) 7- to 15-membered bicyclic spiro-bound heterocyclicring which consists of two spiro-bound (a) 4- to 8-membered monocyclicrings composed of at least one nitrogen atom and carbon atoms”, include,for example, 2,7-diazaspiro[3.5]nonane, 2,8-diazaspiro[4.5]decane,2,7-diazaspiro[4.5]decane, 2,9-diazaspiro[5.5]undecane,2,8-diazaspiro[5.5]undecane, 2,6-diazaspiro[3.5]nonane,3,9-diazaspiro[5.5]undecane, 2,7-diazaspiro[4.4]nonane,1,3,8-triazaspiro[4.5]decane, 1,4,9-triazaspiro[5.5]undecane and thelike.

Examples of “(2) 7- to 15-membered bicyclic spiro-bound heterocyclicring which consists of spiro-bound (a) 4- to 8-membered monocyclic ringcomposed of at least one nitrogen atom and carbon atoms, and (b) 4- to8-membered monocyclic ring composed of at least one nitrogen atom, oneoxygen atom and carbon atoms” include 1-oxa-4,9-diazaspiro[5.5]undecane,1-oxa-4,8-diazaspiro[5.5]undecane and the like.

Examples of “(3) 7- to 15-membered bicyclic spiro-bound heterocyclicring which consists of two spiro-bound (b) monocyclic rings composed ofat least one nitrogen atom, one oxygen atom and carbon atoms” include2,9-dioxa-5,12-diazaspiro[6.6]tridecane and the like.

Also, the “substituent” in the group J is not specifically limited. Thesubstituent includes, for example, substituents exemplified as for T,and these optional substituents may be substituted on the substitutableposition and the number of substituents is from 1 to 5. When J issubstituted with a group having a basic group, optional substituents maybe substituted on the substitutable position and the number ofsubstituents is from 1 to 5. Furthermore, the “aliphatic hydrocarbongroup”, the “cyclic group” and the “group having a basic group” in Jhave the same meanings as in the “aliphatic hydrocarbon group”, the“cyclic group” and the “group having a basic group” in A¹ and A²,respectively.

In the present specification, the “C3-10 monocyclic or bicycliccarbocyclic ring” represented by ring J¹ includes a C3-10 monocyclic orbicyclic unsaturated carbocyclic ring, and partially or completelysaturated one thereof. Examples thereof include, for example, benzene,azulene, naphthalene, cyclopropane, cyclobutane, cyclopentane,cyclohexane, cycloheptane, cyclooctane, cyclononane, cyclodecane,cyclohexene, cycloheptene, cyclooctene, cyclopentadiene, cyclohexadiene,cycloheptadiene, cyclooctadiene, pentalene, perhydropentalene,perhydroazulene, indene, perhydroindene, indane, dihydronaphthalene,tetrahydronaphthalene, perhydronaphthalene, heptalene, perhydroheptaleneand the like.

In the present specification, the “3- to 10-membered monocyclic orbicyclic heterocyclic ring composed of a carbon atom(s), an oxygenatom(s) and/or an optionally oxidized sulfur atom(s)” represented byring J¹ includes a 3- to 10-membered monocyclic or bicyclic unsaturatedheterocyclic ring composed of a carbon atom(s), an oxygen atom(s) and/oran optionally oxidized sulfur atom(s), and partially or completelysaturated one thereof. Examples thereof include, for example, furan,pyran, oxepine, thiophene, thiopyran, thiepine, benzofuran,isobenzofuran, benzothiophene, isobenzothiophene, dithianaphthalene,chromene, benzoxepine, benzothiepine, oxirane, oxetane, dihydrofuran,tetrahydrofuran, dihydropyran, tetrahydropyran, dihydrooxepine,tetrahydrooxepine, perhydrooxepine, thiirane, thietane,dihydrothiophene, tetrahydrothiophene, dihydrothiopyran,tetrahydrothiopyran, dihydrothiepine, tetrahydrothiepine,perhydrothiepine, oxathiane, dihydrobenzofuran, perhydrobenzofuran,dihydroisobenzofuran, perhydroisobenzofuran, dihydrobenzothiophene,perhydrobenzothiophene, dihydroisobenzothiophene,perhydroisobenzothiophene, benzoxathiane, benzodioxepane, dioxolane,dioxane, dithiolane, dithiane, dioxaindane, benzodioxane, chroman,benzodithiolane, benzodithiane and the like.

In the present specification, the “3- to 10-membered monocyclic orbicyclic heterocyclic ring which has at least one nitrogen atom, andalso may have an oxygen atom or an optionally oxidized sulfur atom”represented by ring J¹ includes a 3- to 10-membered monocyclic orbicyclic unsaturated heterocyclic ring which has at least one nitrogenatom, and also may have an oxygen atom(s) and/or an optionally oxidizedsulfur atom(s), and partially or completely saturated one thereof.Examples thereof include, for example, aziridine, azetidine, pyrroline,pyrrolidine, imidazoline, imidazolidine, triazoline, triazolidine,tetrazoline, tetrazolidine, pyrazoline, pyrazolidine, dihydropyridine,tetrahydropyridine, piperidine, dihydropyrazine, tetrahydropyrazine,piperazine, dihydropyrimidine, tetrahydropyrimidine, perhydropyrimidine,dihydropyridazine, tetrahydropyridazine, perhydropyridazine,dihydroazepine, tetrahydroazepine, perhydroazepine, dihydrodiazepine,tetrahydrodiazepine, perhydrodiazepine, dihydrooxazole,tetrahydrooxazole (oxazolidine), dihydroisoxazole, tetrahydroisoxazole(isoxazolidine), dihydrothiazole, tetrahydrothiazole (thiazolidine),dihydroisothiazole, tetrahydroisothiazole (isothiazolidine),dihydrofurazan, tetrahydrofurazan, dihydrooxadiazole,tetrahydrooxadiazole (oxadiazol idine), dihydrooxazine,tetrahydrooxazine, dihydrooxadiazine, tetrahydrooxadiazine,dihydrooxazepine, tetrahydrooxazepine, perhydrooxazepine,dihydrooxadiazepine, tetrahydrooxadiazepine, perhydrooxadiazepine,dihydrothiadiazole, tetrahydrothiadiazole (thiadiazolidine),dihydrothiazine, tetrahydrothiazine, dihydrothiadiazine,tetrahydrothiadiazine, dihydrothiazepine, tetrahydrothiazepine,perhydrothiazepine, dihydrothiadiazepine, tetrahydrothiadiazepine,perhydrothiadiazepine, morpholine, thiomorpholine, indoline,isoindoline, dihydroindazole, perhydroindazole, dihydroquinoline,tetrahydroquinoline, perhydroquinoline, dihydroisoquinoline,tetrahydroisoquinoline, perhydroisoquinoline, dihydrophthalazine,tetrahydrophthalazine, perhydrophthalazine, dihydronaphthyridine,tetrahydronaphthyridine, perhydronaphthyridine, dihydroquinoxaline,tetrahydroquinoxaline, perhydroquinoxaline, dihydroquinazoline,tetrahydroquinazoline, perhydroquinazoline, dihydrocinnoline,tetrahydrocinnoline, perhydrocinnoline, dihydrobenzoxazine,dihydrobenzothiazine, pyrazinomorpholine, dihydrobenzoxazole,perhydrobenzoxazole, dihydrobenzothiazole, perhydrobenzothiazole,dihydrobenzimidazole, perhydrobenzimidazole, dihydrobenzazepine,tetrahydrobenzazepine, dihydrobenzodiazepine, tetrahydrobenzodiazepine,benzodioxepane, dihydrobenzoxazepine, tetrahydrobenzoxazepine, pyrrole,imidazole, triazole, tetrazole, pyrazole, pyridine, pyrazine,pyrimidine, pyridazine, azepine, diazepine, oxazole, isoxazole,thiazole, isothiazole, furazan, oxadiazole, oxazine, oxadiazine,oxazepine, oxadiazepine, thiadiazole, thiazine, thiadiazine, thiazepine,thiadiazepine, indole, isoindole, indolizine, indazole, quinoline,isoquinoline, quinolizine, purine, phthalazine, pteridine,naphthyridine, quinoxaline, quinazoline, cinnoline, benzoxazole,benzothiazole, benzimidazole, benzoxazepine, benzoxadiazepine,benzothiepine, benzothiazepine, benzothiadiazepine, benzoazepine,benzodiazepine, benzofurazan, benzothiadiazole, benzotriazole and thelike.

The “C3-10 monocyclic or bicyclic carbocyclic ring”, “3- to 10-memberedmonocyclic or bicyclic heterocyclic ring composed of a carbon atom(s),an oxygen atom(s) and/or an optionally oxidized sulfur atom(s)”, or “3-to 10-membered monocyclic or bicyclic heterocyclic ring which has atleast one nitrogen atom and also may have an oxygen atom(s) or anoptionally oxidized sulfur atom(s)” in the “C3-10 monocyclic or bicycliccarbocyclic ring substituted with a group having a basic group”, “3- to10-membered monocyclic or bicyclic heterocyclic ring composed of acarbon atom(s), an oxygen atom(s) and/or an optionally oxidized sulfuratom(s), which is substituted with a group having a basic group”, or “3-to 10-membered monocyclic or bicyclic heterocyclic ring which has atleast one nitrogen atom and also may have an oxygen atom(s) or anoptionally oxidized sulfur atom(s), and also may be substituted with agroup” represented by ring J² is as defined above. The “group having abasic group” here has the same meaning as the “group having a basicgroup” in the above described A¹ and A².

In the present specification, the “bridged polycyclic carbocyclic ring”in the “bridged polycyclic carbocyclic ring substituted with a grouphaving a basic group” represented by ring J³ has the same meaning as inthe above-described “bridged polycyclic carbocyclic ring” in the “cyclicgroup”.

In the present specification, examples of the “bridged polycyclicheterocyclic ring composed of a carbon atom(s), an oxygen atom(s) and/oran optionally oxidized sulfur atom(s)” of the “bridged polycyclicheterocyclic ring composed of a carbon atom(s), an oxygen atom(s) and/oran optionally oxidized sulfur atom(s), which is substituted with a grouphaving a basic group” represented by ring J³ include, for example,oxabicyclo[2.2.1]heptane oxabicyclo[3.2.1]octane and the like.

In the present specification, examples of the “bridged polycyclicheterocyclic ring which has at least one nitrogen atom, and also mayhave an oxygen atom(s) or an optionally oxidized sulfur atom(s)” of the“bridged polycyclic heterocyclic ring which may have at least onenitrogen atom, and also may have an oxygen atom(s) and/or an optionallyoxidized sulfur atom(s), which may be substituted with a group having abasic group” represented by ring J³ include, for example,azabicyclo[2.2.1]heptane, oxabicyclo[2.2.1]heptane,azabicyclo[3.1.1]heptane, azabicyclo[3.2.1]octane,oxabicyclo[3.2.1]octane, azabicyclo[2.2.2]octane,diazabicyclo[2.2.2]octane, 1-azatricyclo[3.3.1.1^(3,7)]decane,3-azabicyclo[3.3.1]nonane, 3,7-diazabicyclo[3.3.1]nonane and the like.

The “group having a basic group” in ring J³ has the same meaning as inthe “group having a basic group” in the above-described A¹ and A².

In the present specification, the “C3-15 monocyclic or condensedcarbocyclic ring” in the “C3-15 monocyclic or condensed carbocyclic ringsubstituted with a group having a basic group” represented by ring J⁴has the same meaning as in the “C3-15 monocyclic or condensedunsaturated carbocyclic ring, and partially or completely saturated onethereof” in the “cyclic group”.

In the present specification, the “3- to 15-membered monocyclic orcondensed heterocyclic ring” of the “3- to 15-membered monocyclic orcondensed heterocyclic ring composed of a carbon atom(s), an oxygenatom(s) and/or an optionally oxidized sulfur atom(s), which issubstituted with a group having a basic group” represented by ring J⁴includes a 3- to 15-membered monocyclic or condensed unsaturatedheterocyclic ring composed of a carbon atom(s), an oxygen atom(s) and/oran optionally oxidized sulfur atom(s), and partially or completelysaturated one thereof. Examples thereof include, for example, furan,pyran, oxepine, thiophene, thiopyran, thiepine, benzofuran,isobenzofuran, benzothiophene, isobenzothiophene, dithianaphthalene,chromene, benzoxepine, benzothiepine, dibenzofuran, xanthene,dibenzothiophene, phenoxathiin, thianthrene, oxirane, oxetane,dihydrofuran, tetrahydrofuran, dihydropyran, tetrahydropyran,dihydrooxepine, tetrahydrooxepine, perhydrooxepine, thiirane, thietane,dihydrothiophene, tetrahydrothiophene, dihydrothiopyran,tetrahydrothiopyran, dihydrothiepine, tetrahydrothiepine,perhydrothiepine, oxathiane, dihydrobenzofuran, perhydrobenzofuran,dihydroisobenzofuran, perhydroisobenzofuran, dihydrobenzothiophene,perhydrobenzothiophene, dihydroisobenzothiophene,perhydroisobenzothiophene, benzoxathiane, benzodioxepane,dihydrodibenzofuran, dihydrodibenzothiophene, tetrahydrodibenzofuran,tetrahydrodibenzothiophene, perhydrodibenzofuran,perhydrodibenzothiophene, dioxolane, dioxane, dithiolane, dithiane,dioxaindane, benzodioxane, chroman, benzodithiolane, benzodithiane andthe like.

In the present specification, the “3- to 15-membered monocyclic orcondensed heterocyclic ring which has at least one nitrogen atom andalso may have an oxygen atom(s) and/or an optionally oxidized sulfuratom(s)” of the “3- to 15-membered monocyclic or condensed heterocyclicring which has at least one nitrogen atom and also may have an oxygenatom(s) and/or an optionally oxidized sulfur atom(s), which may besubstituted with a group having a basic group” represented by ring J⁴includes a monocyclic or condensed 3- to 15-membered unsaturatedheterocyclic ring which has at least one nitrogen atom and also may havean oxygen atom(s) and/or an optionally oxidized sulfur atom(s), andpartially or completely saturated one thereof. Examples thereof include,for example, pyrrole, imidazole, triazole, tetrazole, pyrazole,pyridine, pyrazine, pyrimidine, pyridazine, azepin, diazepin, oxazole,isoxazole, thiazole, isothiazole, furazan, oxadiazole, oxazine,oxadiazine, oxazepine, oxadiazepine, thiadiazole, thiazine, thiadiazine,thiazepine, thiadiazepin, indole, isoindole, indolizine, indazole,quinoline, isoquinoline, quinolizine, purine, phthalazine, pteridine,naphthyridine, quinoxaline, quinazoline, cinnoline, benzoxazole,benzothiazole, benzimidazole, benzoxazepine, benzoxadiazepine,benzothiazepin, benzothiadiazepine, benzoxazepine, benzodiazepine,benzofurazan, benzothiadiazole, benzotriazole, carbazole, β-carboline,acridine, phenazine, phenothiazine, phenoxazine, phenanthridine,phenanthroline, perimidine, aziridine, azetidine, pyrroline,pyrrolidine, imidazoline, imidazolidine, triazoline, triazolidine,tetrazoline, tetrazolidine, pyrazoline, pyrazolidine, dihydropyridine,tetrahydropyridine, piperidine, dihydropyrazine, tetrahydropyrazine,piperazine, dihydropyrimidine, tetrahydropyrimidine, perhydropyrimidine,dihydropyridazine, tetrahydropyridazine, perhydropyridazine,dihydroazepine, tetrahydroazepine, perhydroazepine, dihydrodiazepine,tetrahydrodiazepine, perhydrodiazepine, dihydrooxazole,tetrahydrooxazole (oxazolidine), dihydroisoxazole, tetrahydroisoxazole(isoxazolidine), dihydrothiazole, tetrahydrothiazole (thiazolidine),dihydroisothiazole, tetrahydroisothiazole (isothiazolidine),dihydrofurazan, tetrahydrofurazan, dihydrooxadiazole,tetrahydrooxadiazole (oxadiazolidine), dihydrooxazine,tetrahydrooxazine, dihydrooxadiazine, tetrahydrooxadiazine,dihydrooxazepine, tetrahydrooxazepine, perhydrooxazepine,dihydrooxadiazepine, tetrahydrooxadiazepine, perhydrooxadiazepine,dihydrothiadiazole, tetrahydrothiadiazole (thiadiazolidine),dihydrothiazine, tetrahydrothiazine, dihydrothiadiazine,tetrahydrothiadiazine, dihydrothiazepine, tetrahydrothiazepine,perhydrothiazepine, dihydrothiadiazepine, tetrahydrothiadiazepine,perhydrothiadiazepine, morpholine, thiomorpholine, indoline,isoindoline, dihydroindazole, perhydroindazole, dihydroquinoline,tetrahydroquinoline, perhydroquinoline, dihydroisoquinoline,tetrahydroisoquinoline, perhydroisoquinoline, dihydrophthalazine,tetrahydrophthalazine, perhydrophthalazine, dihydronaphthyridine,tetrahydronaphthyridine, perhydronaphthyridine, dihydroquinoxaline,tetrahydroquinoxaline, perhydroquinoxaline, dihydroquinazoline,tetrahydroquinazoline, perhydroquinazoline, dihydrocinnoline,tetrahydrocinnoline, perhydrocinnoline, dihydrobenzoxazine,dihydrobenzothiazine, pyrazinomorpholine, dihydrobenzoxazole,perhydrobenzoxazole, dihydrobenzothiazole, perhydrobenzothiazole,dihydrobenzimidazole, perhydrobenzimidazole, dihydrobenzazepine,tetrahydrobenzazepine, dihydrobenzodiazepine, tetrahydrobenzodiazepine,dihydrobenzoxazepine, tetrahydrobenzoxazepine, dihydrocarbazole,tetrahydrocarbazole, perhydrocarbazole, dihydroacridine,tetrahydroacridine, perhydroacridine, hexahydro-1H-pyrrolidine,octahydrocyclopenta[c]pyrrole, octahydrocyclopenta[b]pyrrole,octahydropyrrolo[3,2-b]pyrrole, octahydropyrrolo[3,4-c]pyrrole,hexahydro-2H-furo[3,2-b]pyrrole, hexahydro-2H-thieno[3,2-b]pyrrole,decahydroquinoline, decahydro-2,6-naphthylidine,octahydro-2H-quinolidine, octahydro-1H-pyrido[1,2-c]pyrimidine,octahydro-2H-1,4-benzooxazine, decahydro-1,5-naphthylidine,octahydro-1H-pyrrolo[3,4-b]pyridine, octahydro-1H-pyrrolo[3,4-c]pyridineand the like.

The “group having a basic group” in ring J⁴ has the same meaning as the“group having a basic group” in the above-described A¹ and A².

In the specification,

wherein L^(A1) represents -(aliphatic hydrocarbon having 1 to 3 carbonatom(s) which may have a substituent(s))-(nitrogen atom which may have asubstituent(s))-; ring J^(1a) and ring J^(2a) each independentlyrepresents (i) a C3-10 monocyclic or bicyclic carbocyclic ring, or (ii)a 3- to 10-membered monocyclic or bicyclic heterocyclic ring composed ofa carbon atom(s), an oxygen atom(s) and/or an optionally oxidized sulfuratom(s); R^(A) represents a group having a basic group; ring J^(1A) andring J^(2A) may have a substituent(s) in substitutable number on thesubstitutable position and, when two or more substituents are present,plural substituents may be the same or different, provided that (anitrogen atom which may have a substituent) in L^(A) is bonded to ringJ¹,

wherein L^(A2) represents a divalent aliphatic hydrocarbon group having1 to 4 carbon atom(s) which may have a substituent(s); ring J^(1b)represents a 3- to 10-membered monocyclic or bicyclic heterocyclic ringwhich has at least one nitrogen atom and may also have an oxygen atom(s)and/or an optionally oxidized sulfur atom(s); ring J^(1b) may have asubstituent(s) in substitutable number on the substitutable positionand, when two or more substituents are present, plural substituents maybe the same or different; other symbols are as defined above,

wherein ring J^(2b) represents a 3- to 10-membered monocyclic orbicyclic heterocyclic ring which has at least one nitrogen atom and alsomay have an oxygen atom(s) or an optionally oxidized sulfur atom(s),which may be substituted with a group having a basic group; ring J^(2b)may have a substituent(s) in substitutable number on the substitutableposition and, when two or more substituents are present, pluralsubstituents may be the same or different; other symbols are as definedabove; or

wherein all symbols are as defined above.

includes, for example,

wherein all symbols are as defined above,

includes, for example,

wherein all symbols are as defined above, with the proviso that L^(A2)may be a substituent of a nitrogen atom of —NH—,

includes, for example,

wherein all symbols are as defined above, with the proviso that anitrogen atom of —NH— may have a substituent, and

includes, for example,

wherein all symbols are as defined above, with the proviso that L^(A2)may be a substituent of a nitrogen atom of —NH— and a nitrogen atom of—NH— may have a substituent.

In the present specification, L^(A1) has the same meaning as in the“-(aliphatic hydrocarbon having 1 to 3 carbon atoms(s) which may have asubstituent(s))-(nitrogen atom which may have a substituent(s))-” in theabove described L^(A), and L^(A2) has the same meaning as in the“-(aliphatic hydrocarbon having 1 to 3 carbon atoms(s) which may have asubstituent(s))-(a nitrogen atom which may have a substituent)-” in theabove described L^(A).

In the present specification, the “(i) C3-10 monocyclic or bicycliccarbocyclic ring or (ii) 3- to 10-membered monocyclic or bicyclicheterocyclic ring composed of a carbon atom(s), an oxygen atom(s) and/oran optionally oxidized sulfur atom(s)” represented by ring J^(1A) andring J^(2A) has the same meaning as in the “(i) C3-10 monocyclic orbicyclic carbocyclic ring or (ii) 3- to 10-membered monocyclic orbicyclic heterocyclic ring composed of a carbon atom(s), an oxygenatom(s) and/or an optionally oxidized sulfur atom(s)” in ring J¹.

In the present specification, the “3- to 10-membered monocyclic orbicyclic heterocyclic ring which has at least one nitrogen atom and alsomay have an oxygen atom(s) or an optionally oxidized sulfur atom(s)”represented by ring J^(1b) has the same meaning as in the “3- to10-membered monocyclic or bicyclic heterocyclic ring which has at leastone nitrogen atom, and also may have an oxygen atom(s) and/or anoptionally oxidized sulfur atom(s)” in ring J¹.

In the present specification, “3- to 10-membered monocyclic or bicyclicheterocyclic ring which has at least one nitrogen atom and also may havean oxygen atom(s) or an optionally oxidized sulfur atom(s), and whichmay be substituted with a group having a basic group” represented byring J^(2b) has the same meaning as in the “3- to 10-membered monocyclicor bicyclic heterocyclic ring which has at least one nitrogen atom andalso may have an oxygen atom(s) or an optionally oxidized sulfuratom(s), and which may be substituted with a group having a basic group”in ring J².

In the present specification, the “mono- or di-substituted amino group”in the “C4-7 monocyclic carbocyclic ring substituted with a mono- ordi-substituted amino group” represented by J^(1B) has the same meaningas in the “a mono- or di-substituted amino group” exemplified as for the“basic group”. Also, examples of the “C4-7 monocyclic carbocyclic ring”include cyclobutane, cyclopentane, cyclohexane, cycloheptane,cyclopentene, cyclohexene, cycloheptene, cyclopentadiene,cyclohexadiene, cycloheptadiene, benzene ring and the like.

In the present specification, the “group having a basic group” of R^(A)has the same meaning as in the “group having a basic group” in A¹ andA².

In the present specification, the “substituent” of the “may have asubstituent(s) in substitutable number on the substitutable position” ofring J¹, ring J², ring J³, ring J⁴, ring J^(1a), ring J^(1b), ringJ^(2a) and ring J^(2b) is not specifically limited. Examples thereofinclude those exemplified as for T, and these optional substituents maybe substituted on the substitutable position and the number ofsubstituents is preferably from 1 to 8, and more preferably from 1 to 5.When ring J², ring J³, ring J⁴ and ring J^(2b) are substituted with agroup having a basic group, these optional substituents may besubstituted on the substitutable position and the number of substituentsis preferably from 1 to 8, and more preferably from 1 to 4.

In the present specification, examples of the “substituent” representedby R include substituents exemplified as for T, a carboxyl group whichmay be protected with a protective group, a hydroxyl group which may beprotected with a protective group, a C1-4 alkyl group which may besubstituted with a hydroxyl group which may be protected with aprotective group, and an amino group which may be protected with aprotective group.

Herein, the “protective group” includes, for example, an aliphatichydrocarbon group which may have a substituent(s), and examples of the“substituent” here include an oxo group, a thioxo group, a carbamoylgroup, for example, an aminocarbonyl group substituted with an aliphatichydrocarbon group, such as an N-butylaminocarbonyl group, anN-cyclohexylmethylaminocarbonyl group, an N-cyclohexylaminocarbonylgroup, and a phenylcarbonyl group. The “aliphatic hydrocarbon group” inthe “an aliphatic hydrocarbon group which may have a substituent(s)” inthe “protective group” has the same meaning as in the “aliphatichydrocarbon group”, and the “substituents” may be substituted on thesubstitutable position and the number of substituents is from 1 to 5,and preferably from 1 to 2, and plural substituents may be the same ordifferent. These optional substituents may be substituted on thesubstitutable position and the number of substituents is 1.

In R, examples of the “carboxyl group which may be protected with aprotective group” include a C1-4 alkoxycarbonyl group (for example,methoxycarbonyl, ethoxycarbonyl, etc.), examples of the “C1-4 alkylgroup which may be substituted with a hydroxyl group which may beprotected with a protective group” includes a C1-4 alkyl group, a C1-4hydroxyalkyl group (hydroxymethyl, hydroxyethyl, hydroxypropyl,hydroxybutyl group, and isomer groups thereof, etc.), and an a C1-4 acylgroup (for example, formyl, acetyl, propionyl, butyryl group, etc.).Examples of the “hydroxyl group which may be protected with a protectivegroup” includes a C1-4 alkoxy group (for example, a linear or branchedC1-4 alkoxy group such as methoxy, ethoxy, n-propoxy, isopropoxy,n-butoxy, isobutoxy, sec-butoxy, tert-butoxy group, etc.), and a C1-8acyloxy group (for example, formyloxy, acetyloxy, propanoyloxy,butanoyloxy, pentanoyloxy, hexanoyloxy, octanoyloxy group, isomer groupsthereof, etc.) Examples of the “amino group which may be protected witha protective group” include an amino group, a mono- or di-C1-6alkylamino group (for example, methylamino, ethylamino, n-propylamino,isopropylamino, n-butylamino, isobutylamino, tert-butylamino,n-pentylamino, isopentylamino, neopentylamino, n-hexylamino,dimethylamino, diethylamino, dipropylamino, N-ethyl-N-methylamino, etc.)and a C2-8 acylamino group (for example, acetylamino, propionylamino,butyryl amino, valerylamino, hexanoylamino, heptanoylamino,octanoylamino, isomers thereof, etc.).

In the present specification, the “carboxyl group which may be protectedwith a protective group”, the “hydroxyl group which may be protectedwith a protective group”, the “C1-4 alkyl group which may be substitutedwith a hydroxyl group which may be protected with a protective group”and the “amino group which may be protected with a protective group”represented by R^(c) have the same meanings as in the “carboxyl groupwhich may be protected with a protective group”, the “hydroxyl groupwhich may be protected with a protective group”, the “C1-4 alkyl groupwhich may be substituted with a hydroxyl group which may be protectedwith a protective group” and the “amino group which may be protectedwith a protective group” in the above described R.

In the present specification, examples of the “C1-4 alkyl groupsubstituted with a hydroxyl group” represented by R^(1C) includehydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl and the like.Examples of the “C1-4 alkoxy group” in the “C1-4 alkyl group substitutedwith a C1-4 alkoxy group” represented by R^(1C) include linear orbranched C1-4 alkoxy groups such as methoxy, ethoxy, n-propoxy,isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy group and thelike. Examples of the “C1-4 alkyl group substituted with a C1-4 alkoxygroup” include methoxymethyl, methoxyethyl, ethoxyethyl and the like.

In the present specification, the “carbon atom which may have asubstituent(s)” represented by G^(A) represents, in addition to —CH₂—,those wherein two hydrogen atoms in the “—CH₂-” group are, eachindependently, optionally substituted with an aliphatic hydrocarbongroup, a C1-8 alkylidene group, an aliphatic hydrocarbon groupsubstituted with a cyclic group, a hydroxyl group, an —O-aliphatichydrocarbon group, a mercapto group, a —S— aliphatic hydrocarbon group,a —S(O)— aliphatic hydrocarbon-cyclic group, a —SO₂-aliphatichydrocarbon group, a —CO-aliphatic hydrocarbon group, a carboxyl group,a —COO-aliphatic hydrocarbon group, a cyano group, a nitro group, ahalogen atom, a methyl group which is substituted with 1 to 3 halogenatom(s), or a methoxy group which is substituted with 1 to 3 halogenatom(s) among those exemplified as for T, and those wherein two hydrogenatoms are substituted with an oxo group.

In the present specification, the “nitrogen atom which may have asubstituent(s)” represented by G^(A) represents, in addition to —NH—,those wherein a hydrogen atom in the “—NH—” group are optionallysubstituted with an aliphatic hydrocarbon group, an aliphatichydrocarbon group substituted with a cyclic group, an —O-aliphatichydrocarbon group, a —SO₂-aliphatic hydrocarbon group, a —CO-aliphatichydrocarbon group, a —COO-aliphatic hydrocarbon group, a nitro group, ora methyl group which is substituted with 1 to 3 halogen atom(s) amongthose exemplified as for T.

In the present specification, the “carbon atom which may have asubstituent(s)” represented by G^(1A), G^(2A) and G^(3A) represents thesame meaning as in the “carbon atom which may have a substituent(s)”defined in G^(A).

In the present specification, the “nitrogen atom which may have asubstituent(s)” represented by G^(2A) represents, in addition to —NH—,those wherein a hydrogen atom in the “—NH—” group is optionallysubstituted with a C1-4 alkyl group which may have a substituent.Herein, examples of the substituent of the “C1-4 alkyl group which mayhave a substituent” include a 3- to 8-membered monocyclic heterocyclicring, and (a) a hydroxyl group, (b) an amino group and (c) a carboxylgroup, which may be protected with a protective group, respectively.Herein, examples of the “3- to 8-membered monocyclic heterocyclic ring”include rings exemplified as for the “3- to 8-membered monocyclicheterocyclic ring” of the “divalent 3- to 8-membered monocyclic groupwhich may have a substituent(s)”. Optional substituents exemplified asfor the “substituent” of the “C1-4 alkyl group which may have asubstituent(s)” may be substituted on the substitutable position and thenumber of substituents is from 1 to 4, and preferably from 1 to 2.Herein, the “protective group” includes, for example, an aliphatichydrocarbon group which may have a substituent(s). Examples of the“substituent” here include an oxo group, a thioxo group, a carbamoylgroup, an aminocarbonyl group substituted with an aliphatic hydrocarbongroup, such as an N-butylaminocarbonyl group, anN-cyclohexylmethylaminocarbonyl group, an N-cyclohexylaminocarbonylgroup, or a phenylcarbonyl group. The “aliphatic hydrocarbon group” inthe “aliphatic hydrocarbon group which may have a substituent(s)” as the“protective group” has the same meaning as in the “aliphatic hydrocarbongroup” and the “substituent” may be substituted on the substitutableposition and the number of substituents is from 1 to 5, and preferablyfrom 1 to 2 and plural substituents may be the same or different. Theseoptional substituents may be substituted on the substitutable positionand the number of substituents is 1.

In the present specification, the “optionally oxidized sulfur atom”represented by G^(2A) means —S—, —SO— and —SO₂—.

In the present specification, the “substituent” represented by R¹includes, for example, substituents exemplified as for the abovedescribed T.

In the present specification, the “C1-4 alkyl group” represented by R³has the same meaning as described above.

In the present specification, the “C5-7 saturated monocyclic carbocyclicring” represented by R³ includes, for example, cyclopentane, cyclohexaneand cycloheptane rings.

In the present specification, examples of the substituents representedby R⁴ and R⁵ include substituents exemplified as for the substituent T.

In the present specification, examples of the “substituent” representedby R⁶ include an aliphatic hydrocarbon group, an aliphatic hydrocarbongroup substituted with a cyclic group, an —O-aliphatic hydrocarbongroup, a —SO₂-aliphatic hydrocarbon group, a —CO-aliphatic hydrocarbongroup, a —COO-aliphatic hydrocarbon group, a nitro group, a methyl groupwhich is substituted with 1 to 3 halogen atoms and the like. Examples ofthe substituent include substituents which are defined and exemplifiedin the above described T.

In the present specification, the “carbon atom which may have asubstituent(s)” represented by L^(2B) has the same meaning as in the“divalent carbon atom which may have a substituent(s)”.

In the present invention, all isomers are included unless otherwisespecified. For example, an alkyl group, an alkenyl group, an alkynylgroup, an alkylene group, an alkenylene group, an alkynylene group, analkylidene group and the like include those which are linear andbranched. Furthermore, all of isomers (E-, Z-, cis-, and trans-isomers)on the double bond, ring and condensed ring, isomers (R-isomer,S-isomer, α,β configuration, enantiomer, and diastereomer) due to thepresence of asymmetric carbon, optically active substances with opticalrotation (D-, L-, d-, and I-compounds), polar compounds (high polarcompound and low polar compound) generated by chromatographicseparation, equilibrium compounds, rotational isomers, mixtures in anoptional mixing ratio and racemic mixtures are included in the presentinvention.

[Salts]

Salts of the compound represented by formula (I) include all of nontoxicsalts and pharmaceutically acceptable salts. The pharmaceuticallyacceptable salt is preferably a water soluble salt which shows lesstoxicity. Examples of the suitable salt of the compound represented byformula (I) include salts of alkali metal (potassium, sodium, lithium,etc.), salts of alkali earth metal (calcium, magnesium, etc.), ammoniumsalts (tetramethylammonium salt, tetrabutylammonium salt, etc.), saltsof organic amine (triethylamine, methylamine, dimethylamine,cyclopentylamine, benzylamine, phenethylamine, piperidine,monoethanolamine, diethanolamine, tris(hydroxymethyl)methylamine,lysine, arginine, N-methyl-D-glucamine, etc.), acid addition salts[inorganic acid salts (hydrochloride, hydrobromide, hydroiodide,sulfate, phosphate, nitrate, etc.), and organic acid salts (acetate,trifluoroacetate, lactate, tartrate, oxalate, fumarate, maleate,benzoate, citrate, methanesulfonate, ethanesulfonate, benzenesulfonate,toluenesulfonate, isethionate, glucuronate, gluconate, etc.)] and thelike.

Furthermore, salts include quaternary ammonium salts. The quaternaryammonium salt is obtained by quaternizing a nitrogen atom of thecompound represented by formula (I) with a R⁰ group (R⁰ group representsa C1-8 alkyl group, or a C1-8 alkyl group substituted with a phenylgroup).

Also, salts include N-oxide. The compound of the present invention canbe converted into N-oxide by an optional method. N-oxide is obtained byoxidizing a nitrogen atom of the compound represented by formula (I).

Examples of suitable solvate of the compound represented by formula (I)include solvates such as water, alcoholic solvent (for example,methanol, ethanol, etc.) and the like. The solvate is preferablynontoxic and water soluble. The solvate of the compound of the presentinvention also includes solvates of alkali (earth) metal salts, ammoniumsalts, salts of organic amine, and acid addition salts of the compoundof the present invention.

The compound of the present invention can be converted into the abovesalts and solvates by a known method.

[Prodrugs]

A prodrug of the compound represented by formula (I) means a compoundwhich is converted into the compound represented by formula (I) in theliving body by the reaction with an enzyme, gastric acid or the like.Examples of the prodrug of the compound represented by formula (I)include compound wherein an amino group is acylated, alkylated, orphosphorylated (for example, compound wherein an amino group of thecompound represented by formula (I) is eicosanoylated, alanylated,pentylaminocarbonylated,(5-methyl-2-oxo-1,3-dioxolen-4-yl)methoxycarbonylated,tetrahydrofuranylated, pyrrolidylmethylated, pivaloyloxymethylated,acetoxymethylated, tert-butylated, etc.) when the compound representedby formula (I) has an amino group; compound wherein a hydroxyl group isacylated, alkylated, phosphorylated, boricated or the like (for example,compound wherein a hydroxyl group of the compound represented by formula(I) is acetylated, palmitoylated, propanoylated, pivaloylated,succinylated, fumarylated, alanylated, dimethylaminomethylcarbonylated,etc.) when the compound represented by formula (I) has a hydroxyl group;and compound wherein a carboxy group is esterificated, amidated or thelike (for example, compound wherein a carboxy group of the compoundrepresented by formula (I) is ethylesterificated, phenylesterificated,carboxymethylesterificated, dimethylaminomethylesterificated,pivaloyloxymethylesterificated,1-{[(ethoxy)carbonyl]oxy}ethylesterificated, phthalidylesterificated,(5-methyl-2-oxo-1,3-dioxolen-4-yl)methylesterificated,1-{[(cyclohexyloxy)carbony]oxy}lethylesterificated, methylamidated,etc.) when the compound represented by formula (I) has a carboxy group.These compounds can be prepared by a per se known method. The prodrug ofthe compound represented by formula (I) may be either of a hydrate and anon-hydrate. Also, the prodrug of the compound represented by formula(I) may be converted into the compound represented by formula (I) underphysiological conditions described in “Development of Drug” published in1990 by Hirokawa Shoten, Vol. 7, “Molecular Design”, pp. 163-198.Furthermore, the compound represented by formula (I) may be labelledwith isotope (for example, ³H, ¹⁴C, ³⁵S, ¹²⁵I, etc.) and the like.

The compound represented by formula (I) of the present invention, a saltthereof, a solvate thereof, or a prodrug thereof (hereinafterabbreviated to a compound of the present invention, sometimes) is acompound which is excellent in solubility and oral absorption andmaintain its pharmacological activity for a long period of time, and isalso less likely to be inhibited by a drug metabolizing enzyme and haslow toxicity. These properties are most important physical, chemical andpharmacological properties required when preparations are developed, andthe inventive compound satisfies these conditions and is expected to beuseful for developing extremely excellent (see The Merck Manual ofDiagnosis and Therapy (17th Ed.), Merck & Co.).

The fact that the compound of the present invention is useful as a drugcan be evaluated by methods described in various tests and biologicalexamples described hereinafter, and methods which can be carried out byappropriately improving the above methods. The fact that the compound ofthe present invention is kinetically excellent in length of half-life inblood, stability in gastrointestinal tract, oral absorption andbioavailability can be easily evaluated by a known method, for example,a method described in “Drug Bioavailability (Science of Evaluation andImprovement)”, Gendai Iryo-sha, published on Jul. 6, 1998.

(I) Evaluation Experiment of an Inhibitory Activity of the Compound ofthe Present Invention Against a Drug-Metabolizing Enzyme

(i) Inhibitory Activity Against Human CYP2A9

An inhibitory activity against CYP2C9 of the compound of the presentinvention can be evaluated by improving accuracy and/or sensitivity ofthe measurement in accordance with the method of Sato et al.(Pharmacokinetic, Xenobio. Metabol. and Dispos., 16(2), pp. 115-126(2001)).

(ii) Inhibitory Activity Against Human CYP3A4

Inhibitory activity against human CYP3A4 of the compound of the presentinvention can be evaluated by an improved method described in DrugMetabolism and Disposition, Vol. 28(12), 1440-1448 (2000).

(II) Evaluation Experiment of a Toxicity of the Compound of the PresentInvention (i) Single Acute Toxicity Test in Rat

The test compound is administered to six-week Crj:CD (SD) rat by singleintravenous dose or single oral administration. Toxicity can beevaluated by contrast with value at no addition of the test compound.Basic evaluation of toxicity can be done by, for example, observation ofperformance status or locomotor activity, etc.

(ii) Evaluation of the Activity of the Compound of the Present InventionAgainst hERG I_(Kr) Current

According to the report by Zou et al. (Biophys. J., Vol. 74, 230-241(1998)), using HEK293 cell overexpressed of human ether-a-go-go-relatedgene (hERG), max tale current of hERG I_(Kr) current induced bydepolarization pulse followed by repolarization pulse is measured bypatch-clamp recording. Rate of change (inhibition rate) is calculated bycomparison max tale current between before addition of the test compoundand 10 minutes after. The influence of the test compound against hERGI_(Kr) current can be evaluated by the inhibition rate

(iii) Evaluation of Action of Compound of the Present Invention Againstphospholipidosis

It is possible to easily evaluate in accordance with the report ofKasahara et al. (Toxicol. Sci., Vol. 90, pp. 1330-141 (2006)) and thereport of Narita at al. (document “in vitro Phospholipidosis DetectionSystem using Fluorescent-Labeled Phospholipids Analogue” distributed inpresentation of results of research of Human Science Synthetic ResearchPromotion Business focusing on Drug Innovation in fiscal year 2003).

(iv) Evaluation of the Influence of a Compound of the Present Inventionon Blood Pressure and Heart Rate

A rat is anesthetized with urethane (1.2 g/kg subcutaneousadministration). After neck midline dissection, a catheter for measuringblood pressure is inserted into a right common carotid artery. Then,after dissecting inguinal region, a catheter for chemical injection isinserted into a femoral vein and fixed. A catheter for measurement ofblood pressure is connected to a pressure transducer and then thepressure waveform is recorded on a thermal writing pen recorder throughan amplifier for strain compression (AP-641G (manufactured by NIHONKOHDEN CORPORATION)). In this case, regarding a heart rate, a valuethrough an cardiotachometer (AT-601G (manufactured by NIHON KOHDENCORPORATION)) using the pressure waveform obtained from the amplifierfor strain compression as a trigger is recorded on a thermal writing penrecorder. The test compound is dissolved in a 10% solubilizingagent/physiological saline solution (volume ratio of polyoxyethylenehydroxystearate:propylene glycol:physiological saline=7:3:190) so as toadjust the concentration to 0.1, 0.3, 1, 3 or 10 mg/mL to preparesolutions. Each solution is intravenous administered at 1 mL/Kg throughthe caudal vein over about 10 seconds. Accumulative administration ofstepwise increasing in dosage is carried out to an individual.

The measuring methods (1) to (2) described above are not limited to themethods described above and a conventional method can be practicallyused based on a basic method. Also, the measuring method may be modifiedto improve accuracy and/or sensitivity of the measurement for evaluatingthe compound of the present invention.

In the formula (I) of the present invention, any of each definition byA¹, A², B¹, B², R, G, E, L and J is preferred. In the following,preferable groups will be listed. The symbols used herein have the samemeaning as described above.

R is preferably a hydrogen atom, an aliphatic hydrocarbon group, analiphatic hydrocarbon group substituted with a cyclic group, a carboxylgroup which may be protected with a protective group, a hydroxyl groupwhich may be protected with a protective group, a C1-4 alkyl group whichmay be substituted with a hydroxyl group which may be protected with aprotective group, and an amino group which may be protected with aprotective group.

A¹ and A² each is preferably a basic group, and more preferably anitrogen-containing heterocyclic ring which may have a substituent(s).The “nitrogen-containing heterocyclic ring group” herein is preferablypyrrole, imidazole, triazole, pyrazole, pyridine, pyrazine, pyrimidine,benzimidazole, azabenzimidazole, or tetrahydroquinoline ring, morepreferably imidazole or benzimidazole ring, and particularly preferablyimidazol-2-yl or benzoimidazol-2-yl. The “substituent” herein ispreferably absence or an aliphatic hydrocarbon group, more preferablyabsence, a C1-8 alkyl group or the like, and particularly preferablyabsence or a methyl group, and most preferably absence. A¹ and A² may bethe same or different.

B¹ and B² each is preferably a spacer having a main chain of 1 atom,more preferably a carbon atom which may have a substituent(s), andparticularly preferably —CH₂—. The “substituent” herein is preferablyabsence or a methyl group and more preferably absence. B¹ and B² may bethe same or different.

G is preferably, for example, a bond, a carbon atom which may have asubstituent(s), or a nitrogen atom which may have a substituent. The“substituent” here is preferably absence, a hydroxyl group or a methylgroup, and more preferably a hydroxyl group or absence. G is morepreferably —CO—, —CH₂—, —CH(OH)—, or —NH—.

E is preferably, for example, a divalent aliphatic hydrocarbon grouphaving 1 to 4 carbon atom(s) which may have a substituent(s), a divalent3- to 8-membered monocyclic group which may have a substituent(s), or-(a spacer having a main chain of 1 to 2 atom(s))-(a 3- to 8-memberedmonocyclic group which may have a substituent(s))-. The -(a 3- to8-membered monocyclic group which may have a substituent(s))- has thesame meaning as in the divalent 3- to 8-membered monocyclic groupwherein a bond of the right side of the group is bonded to L. Morepreferably, it is a divalent 3- to 8-membered monocyclic group which mayhave a substituent(s) or -(a spacer having a main chain of 1 to 2atom(s))-(a 3- to 8-membered monocyclic group which may have asubstituent(s))-. Herein, the “spacer having a main chain of 1 to 2atom(s)” means the space wherein 1 to 2 atom(s) of the main chain arearranged in a line. Herein, “number of atoms of main chain” is countedso that the number of atoms of the main chain is minimized. The “spacerhaving a main chain of 1 to 2 atom(s)” includes, for example, a divalentgroup composed of 1 to 2 groups selected optionally from —O—, —S—, —CO—,—SO—, —SO₂—, divalent nitrogen atom which may have a substituent,divalent aliphatic hydrocarbon group having one carbon atom which mayhave a substituent(s), wherein 1 to 2 atom(s) of the main chain arearranged in a line. The “divalent nitrogen atom which may have asubstituent(s)” here has the same meaning as described above. Examplesof the “divalent aliphatic hydrocarbon group having 1 to 2 carbonatom(s)” in the “divalent aliphatic hydrocarbon group having 1 to 2carbon atom(s) which may have a substituent(s)” include methylene,ethylene and ethynylene groups. The “substituent” in the “divalentaliphatic hydrocarbon group having 1 to 2 carbon atom(s) which may havea substituent(s) includes, for example, substituents exemplified as forthe above described T, and optional substituents may be substituted onthe substitutable position and the number of substituents is from 1 to2. The “divalent 3- to 8-membered monocyclic group which may have asubstituent(s)” has the same meaning as in those defined in B¹. The “3-to 8-membered monocyclic group” here is preferably, for example, a C5-7monocyclic carbocyclic ring (those having 5 to 7 carbon atoms areselected from the above C3-8 monocyclic carbocyclic ring) and a 5- to7-membered monocyclic heterocyclic ring (those having 5 to 7 memberedrings are selected from the above C3-8 monocyclic carbocyclic ring),more preferably, for example, a cyclopentane, cyclohexane, cyclohexene,cyclohexadiene, benzene, pyridine, pyrazine, pyrimidine, pyridazine,piperidine or piperazine ring, and particularly preferably, for example,a cyclohexane or benzene ring.

The “substituent” in the “divalent 3- to 8-membered monocyclic groupwhich may have a substituent(s)” is preferably, for example, absence, ahalogen atom or a methyl group, and more preferably absence.

The “3- to 8-membered monocyclic group” represented by ring E¹ ispreferably, for example, a C5-7 monocyclic carbocyclic ring (thosehaving 5 to 7 carbon atoms are selected from the above C3-8 monocycliccarbocyclic ring) or a 5- to 7-membered monocyclic heterocyclic ring(those having 5 to 7 membered rings are selected from the above C3-8monocyclic carbocyclic ring), more preferably, for example, acyclopentane, cyclohexane, cyclohexene, cyclohexadiene, benzene,pyridine, pyrazine, pyrimidine, pyridazine, piperidine, or a piperazinering, and particularly preferably, for example, a cyclohexane or benzenering. The “substituent” of the “divalent 3- to 8-membered monocyclicgroup which may have a substituent(s)” is preferably, for example,absence, a halogen atom or a methyl group, and particularly preferablyabsence.

L is preferably a spacer having a main chain of 1 to 2 atom(s). The“spacer having a main chain of 1 to 2 atom(s)” is preferably a divalentgroup composed of 1 to 2 groups selected optionally from —O—, —S—, —CO—,—SO—, —SO₂—, divalent nitrogen atom which may have a substituent,divalent aliphatic hydrocarbon group having one carbon atom which mayhave a substituent(s), wherein 1 to 2 atom(s) of the main chain arearranged in a line, or the like. The “divalent aliphatic hydrocarbongroup having one carbon atom which may have a substituent(s)” is thesame meaning as the “divalent aliphatic hydrocarbon group having onecarbon atom which may have a substituent(s)” of the above describedG^(A). The “divalent nitrogen atom which may have a substituent” is thesame meaning as the “divalent nitrogen atom which may have asubstituent” of the above described G. The L is more preferably —CH₂—,—O—CH₂—, —S—CH₂—, —NH—CH₂—, —CH₂—CH₂—, —CH═CH—, —C≡C—, —CH₂—O—, —CH₂—S—,—CH₂—NH—, —CONH—, —SO₂—NH—, —NHCO— or —NHSO₂—, and particularlypreferably —CH₂—, —CONH—, —CH₂—NH—, —O—CH₂—, —S—CH₂—, —CH₂—CH₂-(J isbonded to the right side). A bond is also preferable.

J is preferably an aliphatic hydrocarbon group which is substituted witha basic group, and also may have a substituent(s); a cyclic group whichis substituted with an aliphatic hydrocarbon group substituted with abasic group, and also may have a substituent(s); or an aliphatichydrocarbon group which is substituted with a cyclic group substitutedwith a basic group, and also may have a substituent(s). The “basicgroup” herein is preferably a mono- or di-substituted amino group, or anitrogen-containing heterocyclic ring which may have a substituent(s).The “mono- or di-substituted amino group” herein is preferably adi-substituted amino group, more preferably dimethylamino, diethylamino,dipropylamino, dibutylamino, or N-cyclohexyl-N-propylamino, andparticularly preferably dipropylamino or N-cyclohexyl-N-propylamino. The“nitrogen-containing heterocyclic ring which may have a substituent(s)”herein is preferably non-substituted nitrogen-containing heterocyclicring, or a nitrogen-containing heterocyclic ring substituted with a C1-8alkyl group or an oxo group, and the “nitrogen-containing heterocyclicring” is preferably a pyrrolidine, piperidine, morpholine,thiomorpholine, perhydrodiazepine, tetrahydroisoquinoline,2,8-diazaspiro[4.5]decane, 1,4,9-triazaspiro[5.5]undecane,3,9-diazaspiro[5.5]undecane, or 2,9-diazaspiro[5.5]undecane ring.

The “aliphatic hydrocarbon group” in the “aliphatic hydrocarbon groupwhich is substituted with a basic group, and also may have asubstituent(s)” or “aliphatic hydrocarbon group which is substitutedwith a cyclic group substituted with a basic group, and also may have asubstituent(s)” herein is preferably a C1-8 alkyl group or a C2-8alkenyl group, and more preferably methyl, ethyl, propyl, butyl, pentyl,or hexyl. The “cyclic group” in the “cyclic group which is substitutedwith an aliphatic hydrocarbon group substituted with a basic group, andalso may have a substituent(s)” is preferably a C5-7 monocycliccarbocyclic ring (ring having 5 to 7 carbon atoms is selected from amongthe above described C3-15 monocyclic or polycyclic carbocyclic ring) ora 5- to 7-membered monocyclic heterocyclic ring (5- to 7-memberedheterocyclic ring is selected from among the above described 3- to15-membered monocyclic or polycyclic heterocyclic ring), and morepreferably a cyclopentane, cyclohexane, cyclohexene, adamantyl,cyclohexadiene, benzene, pyridine, pyrazine, tetrahydropyran,pyrimidine, pyridazine, piperidine, or piperazine ring. The“substituent” herein is preferably absence, a halogen atom, a methylgroup, a hydroxyl group, an amino group or an oxo group, and morepreferably absence.

Furthermore, J is preferably a “cyclic group which is substituted with agroup having a basic group, and also may have a substituent(s)”, a“spiro-bound cyclic group which may be substituted with a group having abasic group, and also may have a substituent(s)”, or a “bridged cyclicgroup which may be substituted with a group having a basic group, andalso may have a substituent(s)”. The “cyclic group” or “spiro-boundcyclic group”, or “bridged cyclic group” is preferably (1) a spiro-boundcyclic group, (2) a bridged polycyclic carbocyclic ring, (3) a bridgedpolycyclic heterocyclic ring composed of a carbon atom(s), an oxygenatom(s) and/or an optionally oxidized sulfur atom(s), (4) a bridgedpolycyclic heterocyclic ring which has at least one nitrogen atom, andalso may have an oxygen atom(s) and/or an optionally oxidized sulfuratom(s), (5) a C3-15 monocyclic or condensed carbocyclic ring, (6) a 3-to 15-membered monocyclic or condensed heterocyclic ring composed of acarbon atom(s), an oxygen atom(s) and/or an optionally oxidized sulfuratom(s), or (7) a 3- to 15-membered monocyclic or condensed heterocyclicring which has at least one nitrogen atom, and also has a carbonatom(s), oxygen atom(s) and/or an optionally oxidized sulfur atom(s).

The “spiro-bound cyclic group” is preferably 2,7-diazaspiro[3.5]nonane,2,8-diazaspiro[4.5]decane, 2,7-diazaspiro[4.5]decane,2,9-diazaspiro[5.5]undecane, 2,8-diazaspiro[5.5]undecane,3,9-diazaspiro[5.5]undecane, 2,7-diazaspiro[4.4]nonane,1,2-dihydrospiro[indole-3,4′-piperidine],2,3-dihydro-1H-spiro[isoquinoline-4,4′-piperidine],1′,4′-dihydro-2′H-spiro[piperidine-4,3′-quinoline],2′,3′-dihydro-1′H-spiro[piperidine-4,4′-quinoline],8-azaspiro[4.5]decane, 8-azaspiro[4.5]decane, 7-azaspiro[4.5]decane,3-azaspiro[5.5]undecane, 2-azaspiro[5.5]undecane,1-oxa-4,8-diazaspiro[5.5]undecane, 1-oxa-4,9-diazaspiro[5.5]undecane,3,4-dihydrospiro[chromene-2,4′-piperidine], 2-azaspiro[4.4]nonane,7-azaspiro[3.5]nonane, 2,3-dihydrospiro[indene-1,4′-piperidine],3,4-dihydro-2H-spiro[naphthalene-1,4′-piperidine],3,4-dihydro-1H-spiro[naphthalene-2,4′-piperidine],2-azaspiro[4.5]decane, 2-azaspiro[3.5]nonane,1′,2′-dihydrospiro[cyclohexane-1,3′-indole],2′,3′-dihydro-1′H-spiro[cyclohexane-1,4′-isoquinoline],1′,4′-dihydro-2′H-spiro[cyclohexane-1,3′-quinoline],1,6-diazaspiro[3.4]octane, 1,5-diazaspiro[3.4]octane,1,7-diazaspiro[3.5]nonane, 1,6-diazaspiro[3.5]nonane,1,5-diazaspiro[3.5]nonane, 1,7-diazaspiro[4.4]nonane,1,6-diazaspiro[4.4]nonane, 1,8-diazaspiro[4.5]decane,1,7-diazaspiro[4.5]decane, 2,6-diazaspiro[3.4]octane,1,6-diazaspiro[4.5]decane, 2,6-diazaspiro[3.5]nonane,1,9-diazaspiro[5.5]undecane, 1,8-diazaspiro[5.5]undecane,6-azaspiro[3.5]nonane, 6-azaspiro[3.4]octane, 2-azaspiro[3.4]octane,1,7-diazaspiro[5.5]undecane, 1,4,9-triazaspiro[5.5]undecane,1,3,8-triazaspiro[4.5]decane, 1-thia-4,9-diazaspiro[5.5]undecane,1-thia-4,8-diazaspiro[5.5]undecane, spiro[4.4]nonane, spiro[4.5]decane,spiro[5.5]undecane, spiro[3.4]octane, or spiro[3.5]nonane. The“spiro-bound cyclic group” is more preferably 2,7-diazaspiro[3.5]nonane,2,8-diazaspiro[4.5]decane, 2,7-diazaspiro[4.5]decane,2,9-diazaspiro[5.5]undecane, 2,8-diazaspiro[5.5]undecane,3,9-diazaspiro[5.5]undecane, 2,7-diazaspiro[4.4]nonane,1,2-dihydrospiro[indole-3,4′-piperidine],2,3-dihydro-1H-spiro[isoquinoline-4,4′-piperidine],1′,4′-dihydro-2′H-spiro[piperidine-4,3′-quinoline],2′,3′-dihydro-1′H-spiro[piperidine-4,4′-quinoline],8-azaspiro[4.5]decane, 1-oxa-4,8-diazaspiro[5.5]undecane,1-oxa-4,9-diazaspiro[5.5]undecane,3,4-dihydrospiro[chromene-2,4′-piperidine], 1,6-diazaspiro[3.4]octane,1,5-diazaspiro[3.4]octane, 1,7-diazaspiro[3.5]nonane,1,6-diazaspiro[3.5]nonane, 1,5-diazaspiro[3.5]nonane,1,7-diazaspiro[4.4]nonane, 1,6-diazaspiro[4.4]nonane,1,8-diazaspiro[4.5]decane, 1,7-diazaspiro[4.5]decane,2,6-diazaspiro[3.4]octane, 1,6-diazaspiro[4.5]decane,2,6-diazaspiro[3.5]nonane, 1,9-diazaspiro[5.5]undecane,1,8-diazaspiro[5.5]undecane, 1,7-diazaspiro[5.5]undecane,1,4,9-triazaspiro[5.5]undecane, 1,3,8-triazaspiro[4.5]decane,1-thia-4,9-diazaspiro[5.5]undecane, or1-thia-4,8-diazaspiro[5.5]undecane. The “spiro-bound cyclic group” isparticularly preferably 2,7-diazaspiro[4.5]decane,2,8-diazaspiro[4.5]decane, 2,8-diazaspiro[5.5]undecane,2,9-diazaspiro[5.5]undecane, 2,7-diazaspiro[3.5]nonane, or1-oxa-4,9-diazaspiro[5.5]undecane. The most preferable “spiro-boundcyclic group” is a 2,8-diazaspiro[4.5]decane ring.

The “bridged polycyclic carbocyclic ring” is preferablybicyclo[2.1.1]hexane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane,bicyclo[3.2.1]octane, adamantane, bicyclo[3.3.1]nonane,bicyclo[3.2.1]octane, or bicyclo[3.3.2]decane.

The “bridged polycyclic heterocyclic ring which has at least onenitrogen atom, and also may have an oxygen atom(s) and/or an optionallyoxidized sulfur atom(s)” is preferably1-azatricyclo[3.3.1.1^(3,7)]decane, 3-azabicyclo[3.3.1]nonane, or3,7-diazabicyclo[3.3.1]nonane.

The “7- to 15-membered bicyclic spiro-bound heterocyclic ring wherein aring comprising the spiro-bound heterocyclic ring is a monocyclic ringcomposed of at least one nitrogen atom and carbon atoms, and/or amonocyclic ring composed of at least one nitrogen atom, one oxygen atomand carbon atoms” is preferably a 9- to 11-membered bicyclic spiro-boundheterocyclic ring wherein a ring comprising the spiro-bound heterocyclicring is a monocyclic ring composed of at least one nitrogen atom andcarbon atoms, and/or a monocyclic ring composed of at least one nitrogenatom, one oxygen atom and carbon atoms.

The “9 to 11-membered bicyclic spiro-bound heterocyclic ring wherein aring comprising the spiro-bound heterocyclic ring is a monocyclic ringcomposed of at least one nitrogen atom and carbon atom, and/or amonocyclic ring composed of at least one nitrogen atom, one oxygen atomand carbon atoms” is preferably 2,7-diazaspiro[4.5]decane,2,8-diazaspiro[4.5]decane, 2,8-diazaspiro[5.5]undecane,2,9-diazaspiro[5.5]undecane, 2,7-diazaspiro[3.5]nonane, or1-oxa-4,9-diazaspiro[5.5]undecane. More preferably, it is cyclopentane,cyclohexane, or cyclooctane. Most preferably, it is2,8-diazaspiro[4.5]decane.

The “C3-15 monocyclic or condensed carbocyclic ring” is preferablycyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane,cyclooctane, cyclopentene, cyclohexene, cycloheptene, cyclooctene,cyclopentadiene, cyclohexadiene, cycloheptadiene, cyclooctadiene,benzene, pentalene, perhydropentalene, azulene, perhydroazulene, indene,perhydroindene, indane, naphthalene, dihydronaphthalene,tetrahydronaphthalene, perhydronaphthalene, or1,2,3,5,6,7-hexahydro-s-indacene. More preferably, it is cyclopentane,cyclohexane, or cyclooctane. Most preferably, it is cyclohexane.

The “3- to 15-membered monocyclic or condensed heterocyclic ringcomposed of a carbon atom(s), an oxygen atom(s) and/or an optionallyoxidized sulfur atom(s)” is preferably a partially or completelysaturated 3- to 15-membered monocyclic or condensed heterocyclic ringcomposed of a carbon atom(s), an oxygen atom(s) and/or an optionallyoxidized sulfur atom(s).

The “3- to 15-membered monocyclic or condensed heterocyclic ring whichhas at least one nitrogen atom, and is composed of a carbon atom(s), anoxygen atom(s) and/or an optionally oxidized sulfur atom(s)” ispreferably a partially or completely saturated 3- to 15-memberedmonocyclic or condensed heterocyclic ring which has at least onenitrogen atom, and is composed of a carbon atom(s), an oxygen atomand/or an optionally oxidized sulfur atom(s).

The “substituent” of the “which may be substituted with asubstituent(s)” of ring J¹, ring J², ring J³ and ring J⁴ is preferablyan aliphatic hydrocarbon group, a cyclic group, or an aliphatichydrocarbon group substituted with a cyclic group, and more preferablyan aliphatic hydrocarbon group having 1 to 8 carbon atom(s) or a C3-10monocyclic or bicyclic carbocyclic ring.

The “group having a basic group” of the “which is substituted with agroup having a basic group” or the “which may be substituted with abasic group” of ring J², ring J³ and ring J⁴ is preferably, for example,a mono- or di-substituted amino group, or a nitrogen-containingheterocyclic ring group which may have a substituent(s). The “mono- ordi-substituted amino group” here is preferably a di-substituted aminogroup, more preferably, for example, dimethylamino, diethylamino,dipropylamino, dibutylamino, or N-cyclohexyl-N-propylamino, andparticularly preferably dipropylamino or N-cyclohexyl-N-propylamino.

R^(A) is preferably, for example, a mono- or di-substituted amino group,or a nitrogen-containing heterocyclic ring group which may have asubstituent(s). The “mono- or di-substituted amino group” here ispreferably a di-substituted amino group, and more preferably, forexample, dimethylamino, diethylamino, dipropylamino, dibutylamino, orN-cyclohexyl-N-propylamino.

In the present specification, G^(A) is preferably, for example, a carbonatom which may have a substituent(s), and the substituent of the carbonatom is preferably, for example, absence, a hydroxyl group, an oxogroup, an aliphatic hydrocarbon group, or an aliphatic hydrocarbon groupsubstituted with a cyclic group, and more preferably absence, a hydroxylgroup, or an oxo group.

In the present specification, the “substituent” of the “carbon atomwhich may have a substituent(s)” represented by G^(1A) is preferably,for example, absence, a hydroxyl group, an oxo group, or a C1-4 alkylgroup, an aliphatic hydrocarbon group substituted with a cyclic group,and more preferably, for example, absence or an oxo group.

In the present specification, G^(2A) is preferably a nitrogen atom whichmay have a substituent. Herein, the “substituent” of the “nitrogen atomwhich may have a substituent(s)” is preferably, for example, (1)absence, (2) a C1-4 alkyl group, (3) a C1-4 alkyl group substituted witha hydroxyl group which may be protected with a protective group, (4) aC1-4 alkyl group substituted with an amino group which may be protectedwith a protective group, (5) a C1-4 alkyl group substituted with acarboxyl group which may be protected with a protective group, or (6) aC1-4 alkyl group substituted with a pyrrolidine ring, piperidine ring ora morpholine ring. The protective group here is preferably a C1-4 alkylgroup which may be substituted with an oxo group (for example, acetyl,propionyl, butyryl, isobutyryl, etc.). The “substituent” of “thenitrogen atom which may have a substituent(s)” is more preferably (1) aC1-4 alkyl group substituted with a hydroxyl group (for example,hydroxymethyl, hydroxyethyl, hydroxypropyl, etc.), (2) a C1-4 alkylgroup which is substituted with a hydroxyl group substituted with anacetyl group (for example, acetyloxymethyl, acetyloxyethyl,acetyloxypropyl, etc.), (3) a C1-4 acyl group which may be substitutedwith a C1-4 alkyl group substituted with a hydroxyl group (for example,methanoyl, ethanoyl, propanoyl, butanoyl, hydroxymethylcarbonyl, etc.),(4) a C1-6 alkyl group (for example, aminoethyl, aminopropyl,aminobutyl, aminopentyl, aminohexyl, dimethylaminoethyl,acetylaminoethyl, etc.) substituted with an amino group which may besubstituted with a C1-4 alkyl group or a C1-4 acyl group (for example,formyl, acetyl, propionyl, butyryl, isobutyryl group, etc.), (5) a C1-4alkyl group (for example, pyrrolidinylethyl, morpholinylethyl,pyridinylethyl, etc.) substituted with pyrrolidine, morpholine orpyridine, (6) a C1-4 alkyl group (for example, methoxycarbonyl,ethoxycarbonyl, etc.) substituted with a C1-4 alkoxycarbonyl group, and(7) a C1-4 alkyl group (for example, carboxymethyl, carboxyethyl,carboxypropyl) substituted with a carboxyl group. The “substituent” ofthe “nitrogen atom which may have a substituent(s)” is particularlypreferably a hydroxyethyl, acetyl, methoxyethyl, pyrrolidinylethyl,morpholinylethyl, hydroxymethylcarbonyl, dimethylaminoethyl, oracetylaminoethyl group. As the “nitrogen atom which may have asubstituent(s)”, a non-substituted nitrogen atom is also preferable.

In the present specification, G^(3A) is preferably a carbon atom whichmay have a substituent(s). The “substituent” here is preferably, forexample, absence, a hydroxyl group, oxo group, a C1-4 alkyl group, or analiphatic hydrocarbon group substituted with a cyclic group, and morepreferably, for example, absence or an oxo group.

In the present specification, G is preferably G^(1A)-G^(2A)-G^(3A).G^(1A)-G^(2A)-G^(3A) is preferably, for example, (carbon atom which maybe substituted with an oxo group)-(a nitrogen atom which may have asubstituent)-(carbon atom which may be substituted with an oxo group)and the “substituent” of the “nitrogen atom which may have asubstituent(s)” is preferably, for example, absence, hydroxyethyl,acetyl, methoxyethyl, pyrrolidinylethyl, morpholinyl ethyl,hydroxymethylcarbonyl, dimethylaminoethyl, or acetylaminoethyl group.

In the present specification, L^(A) is preferably, for example,aliphatic hydrocarbon group having 1 to 4 carbon atoms which may have asubstituent(s), more preferably, for example, a carbon atom which mayhave a substituent(s), and particularly preferably, for example, —CH₂—or —CO—.

In the present specification, L^(2B) is preferably, for example, —CH₂—or —CO—, and particularly preferably, for example, —CH₂—.

In the present specification, the “mono- or di-substituted amino group”in “the C4-7 monocyclic carbocyclic ring substituted with a mono- ordi-substituted amino group” represented by J^(1B) is preferably, forexample, a mono- or di-C1-4 alkylamino group (for example, methylamino,ethylamino, propylamino, dimethylamino, diethylamino, etc.), and morepreferably a dipropylamino group. Also, the “C4-7 monocyclic carbocyclicring” is preferably, for example, a cyclohexane ring.

In the present specification, R^(C) is preferably, for example, ahydrogen atom, a cyano group, a C1-4 alkyl group substituted with ahydroxyl group, or a C1-4 alkyl group substituted with a hydroxyl groupprotected with a protective group. The “protective group” here ispreferably a C1-4 alkyl group which may be substituted with an oxogroup. R^(C) is more preferably, for example, a hydrogen atom, a cyano,hydroxymethyl, hydroxyethyl or acetoxymethyl group.

In the present specification, R¹ is preferably an aliphatic hydrocarbongroup, a cyclic group, or an aliphatic hydrocarbon group substitutedwith a cyclic group which may have a substituent(s), and more preferablya C1-4 alkyl group, a monocyclic group, or a C1-4 alkyl groupsubstituted with a monocyclic group which may have a substituent(s). Themonocyclic group is preferably cyclopentane, cyclohexane, or thiophene.The substituent is preferably, for example, a C1-4 alkyl group.

In the present specification, R^(1C) is preferably, for example, ahydrogen atom, a cyano, hydroxymethyl, hydroxyethyl or acetoxymethylgroup.

In the present specification, R² is preferably, for example, a hydrogenatom, a hydroxyethyl, acetyl, methoxyethyl, pyrrolidinylethyl,morpholinylethyl or hydroxymethylcarbonyl group.

In the present specification, R³ is preferably, for example, a C1-4alkyl group or a C5-7 saturated monocyclic carbocyclic ring group, andmore preferably, for example, sec-butyl or cyclohexyl.

In the present specification, R⁴ and R⁵ are preferably, for example, ahydrogen atom, a hydroxyl group or an oxo group.

In the present specification, R⁶ is preferably, for example, a hydrogenatom or an aliphatic hydrocarbon group, and more preferably, forexample, a hydrogen atom or a C1-4 alkyl group.

In the present invention, a compound of formula (I), which contains acombination of preferable groups listed previously, is preferable.

Among compounds represented by formula (I), a preferable compound is acompound represented by formula (I-1):

wherein all symbols are as defined above, formula (I-2):

wherein W¹ represents a spacer having 1 to 2 atoms, and other symbolsare as defined above, a salt thereof, an N-oxide thereof or a solvatethereof, or a prodrug thereof.

Among compounds represented by formula (I), a more preferable compoundis a compound represented by formula (I-1-a):

wherein all symbols are as defined above,formula (I-2-a):

wherein all symbols are as defined above, orformula (I-3):

wherein ring J^(4a) may be substituted with a group having a basic groupor a 3- to 8-membered monocyclic heterocyclic ring which has at leastone nitrogen atom, and also may have an oxygen atom and/or an optionallyoxidized sulfur atom, ring J^(4a) may have a substituent(s) insubstitutable number on the substitutable position and, when two or moresubstituents are present, plural substituents may be the same ordifferent, other symbols are as defined above; Other symbols are asdefined above, formula (I-4):

wherein all symbols are as defined above,formula (I-5):

wherein all symbols are as defined above,or formula (I-6):

wherein all symbols are as defined above, a salt thereof, a solvatethereof, or a prodrug thereof.

In the specification, examples of the “3- to 8-membered monocyclicheterocyclic ring which has at least one nitrogen atom and also may havean oxygen atom(s) and/or an optionally oxidized sulfur atom(s)” of the“3- to 8-membered monocyclic heterocyclic ring which has at least onenitrogen atom and also may have an oxygen atom(s) and/or an optionallyoxidized sulfur atom(s), and which may be substituted with a grouphaving a basic group” represented by ring J^(4a) include, for example,pyrrole, pyridine, azepine, oxazole, isoxazole, thiazole, isothiazole,oxazine, oxazepine, thiazine, thiazepine, aziridine, azetidine,pyrroline, pyrrolidine, dihydropyridine, tetrahydropyridine, piperidine,dihydroazepine, tetrahydroazepine, perhydroazepine, dihydrooxazole,tetrahydrooxazole (oxazolidine) dihydroisoxazole, tetrahydroisoxazole(isoxazolidine), dihydrothiazole, tetrahydrothiazole (thiazolidine),dihydroisothiazole, tetrahydroisothiazole (isothiazolidine),dihydrooxazine, tetrahydrooxazine, dihydrooxazepine,tetrahydrooxazepine, perhydrooxazepine, dihydrothiazine,tetrahydrothiazine, dihydrothiazepine, tetrahydrothiazepine,perhydrothiazepine, morpholine, thiomorpholine rings and the like. The“group having a basic group” here has the same meaning as the “grouphaving a basic group” in the above described A¹ and A².

In the present specification, the “substituent” of the “a substituent(s)in substitutable number on the substitutable position” represented byring J^(4a) is not specifically limited, and includes, for example,substituents exemplified as for the above described T. Optionalsubstituents may be substituted on the substitutable position, and thenumber of substituents may be from 1 to 8, and preferably from 1 to 5.When ring J^(4a) is substituted with a group having a basic group,optional substituents may be substituted on the substitutable position,and the number of substituents may be from 1 to 8, and preferably from 1to 4.

Among compounds represented by formula (I), a more preferable compoundis a compound represented by formula (I-1-a1):

wherein all symbols are as defined above,formula (I-1-a2):

wherein all symbols are as defined above,formula (I-1-a3):

wherein all symbols are as defined above,formula (I-1-a4):

wherein all symbols are as defined above,formula (I-1-a5):

wherein all symbols are as defined above,formula (I-1-a6):

wherein all symbols are as defined above,formula (I-1-a7):

wherein all symbols are as defined above,formula (I-2-a1):

wherein all symbols are as defined above,formula (I-2-a2):

wherein all symbols are as defined above,formula (I-2-a3):

wherein all symbols are as defined above,formula (I-2-a4):

wherein all symbols are as defined above,formula (I-2-a5):

wherein all symbols are as defined above,formula (I-2-a6):

wherein all symbols are as defined above,formula (I-2-a7):

wherein all symbols are as defined above,or, formula (I-4-b):

wherein all symbols are as defined above, a salt thereof, a solvatethereof, or a prodrug thereof.

Among compounds represented by formula (I), a particularly preferablecompound is a compound represented by formula (I-4-b) wherein-L^(B)-B^(B) is:

wherein all symbols are as defined above.

Among compounds represented by formula (I), a most preferable compoundis a compound represented by formula (I-4-a):

wherein all symbols are as defined above, a salt thereof, a solvatethereof, or a prodrug thereof.

Specific examples of the compound of the present invention includecompound shown in the following (1) to (50), compounds described inExamples, salts thereof, N-oxides thereof or solvates thereof orprodrugs thereof:

(1)1-[4-({[4-(dipropylamino)butyl]amino}methyl)phenyl]-3-(1H-imidazol-2-yl)-2-(1H-imidazol-2-ylmethyl)propan-1-one;(2)1-[4-({[4-(dipropylamino)butyl]amino}methyl)phenyl]-3-(1H-imidazol-2-yl)-2-(1H-imidazol-2-ylmethyl)propan-1-ol;(3)N′-{4-[3-(1H-imidazol-2-yl)-2-(1H-imidazol-2-ylmethyl)propyl]benzyl}-N,N-dipropylbutane-1,4-diamine;(4)N-[4-(dipropylamino)butyl]-4-[3-(1H-imidazol-2-yl)-2-(1H-imidazol-2-ylmethyl)propanoyl]benzamide;(5)N-[4-(dipropylamino)butyl]-4-[1-hydroxy-3-(1H-imidazol-2-yl)-2-(1H-imidazol-2-ylmethyl)propyl]benzamide;(6)N-[4-(dipropylamino)butyl]-4-[3-(1H-imidazol-2-yl)-2-(1H-imidazol-2-ylmethyl)propyl]benzamide;(7)1-[4-({[4-(dipropylamino)cyclohexyl]amino}methyl)phenyl]-3-(1H-imidazol-2-yl)-2-(1H-imidazol-2-ylmethyl)propan-1-one;(8)1-{4-[(8-cyclohexyl-2,8-diazaspiro[4.5]dec-2-yl)methyl]phenyl}-3-(1H-imidazol-2-yl)-2-(1H-imidazol-2-ylmethyl)propan-1-one;(9)1-{4-[(8-cyclohexyl-2,8-diazaspiro[4.5]dec-2-yl)methyl]cyclohexyl}-3-(1H-imidazol-2-yl)-2-(1H-imidazol-2-ylmethyl)propan-1-one;(10)N-{4-[(8-cyclohexyl-2,8-diazaspiro[4.5]dec-2-yl)methyl]benzyl}-1,3-di-1H-imidazol-2-ylpropan-2-amine;(11)4-[(8-cyclohexyl-2,8-diazaspiro[4.5]dec-2-yl)methyl]-N-[2-(1H-imidazol-2-yl)-1-(1H-imidazol-2-ylmethyl)ethyl]benzamide;(12)N-{4-[(8-cyclohexyl-2,8-diazaspiro[4.5]dec-2-yl)carbonyl]benzyl}-1,3-di-1H-imidazol-2-ylpropan-2-amine;(13)4-[(8-cyclohexyl-2,8-diazaspiro[4.5]dec-2-yl)methyl]-N-[2-(1H-imidazol-2-yl)-1-(1H-imidazol-2-ylmethyl)ethyl]cyclohexanamine;(14)N-({4-[(8-cyclohexyl-2,8-diazaspiro[4.5]dec-2-yl)methyl]cyclohexyl}methyl)-1,3-di-1H-imidazol-2-ylpropan-2-amine;(15)4-[(8-cyclohexyl-2,8-diazaspiro[4.5]dec-2-yl)carbonyl]-N-[2-(1H-imidazol-2-yl)-1-(1H-imidazol-2-ylmethyl)ethyl]cyclohexanamine;(16)4-[(8-cyclohexyl-2,8-diazaspiro[4.5]dec-2-yl)methyl]-N-[2-(1H-imidazol-2-yl)-1-(1H-imidazol-2-ylmethyl)ethyl]cyclohexanecarboxamide;(17)N-({4-[(8-cyclohexyl-2,8-diazaspiro[4.5]dec-2-yl)carbonyl]cyclohexyl}methyl)-1,3-di-1H-imidazol-2-ylpropan-2-amine;(18)4-[(8-cyclohexyl-2,8-diazaspiro[4.5]dec-2-yl)carbonyl]-N-[2-(1H-imidazol-2-yl)-1-(1H-imidazol-2-ylmethyl)ethyl]cyclohexanecarboxamide;(19)4-[(8-cyclohexyl-2,8-diazaspiro[4.5]dec-2-yl)methyl]-N-[2-(1H-imidazol-2-yl)-1-(1H-imidazol-2-ylmethyl)ethyl]benzenesulfonamide;(20)N′-({1-[3-(1H-imidazol-2-yl)-2-(1H-imidazol-2-ylmethyl)propanoyl]piperidin-4-yl}methyl)-N,N-dipropylcyclohexane-1,4-diamine;(21)8-cyclohexyl-2-({1-[3-(1H-imidazol-2-yl)-2-(1H-imidazol-2-ylmethyl)propanoyl]piperidin-4-yl}methyl)-2,8-diazaspiro[4.5]decane;(22)4-{2-[3-(1H-imidazol-2-yl)-2-(1H-imidazol-2-ylmethyl)propanoyl]-2,8-diazaspiro[4.5]dec-8-yl}-N,N-dipropylbutan-1-amine;(23)N-({1-[(1-cyclohexylpiperidin-4-yl)methyl]piperidin-4-yl}methyl)-3-(1H-imidazol-2-yl)-2-(1H-imidazol-2-ylmethyl)propanamide;(24)1-{5-[(8-cyclohexyl-2,8-diazaspiro[4.5]dec-2-yl)methyl]pyridin-2-yl}-3-(1H-imidazol-2-yl)-2-(1H-imidazol-2-ylmethyl)propan-1-one;(25)1-{6-[(8-cyclohexyl-2,8-diazaspiro[4.5]dec-2-yl)methyl]pyridin-3-yl}-3-(1H-imidazol-2-yl)-2-(1H-imidazol-2-ylmethyl)propan-1-one;(26)1-{5-[(8-cyclohexyl-2,8-diazaspiro[4.5]dec-2-yl)methyl]pyrazin-2-yl}-3-(1H-imidazol-2-yl)-2-(1H-imidazol-2-ylmethyl)propan-1-one;(27)1-{2-[(8-cyclohexyl-2,8-diazaspiro[4.5]dec-2-yl)methyl]pyrimidin-5-yl}-3-(1H-imidazol-2-yl)-2-(1H-imidazol-2-ylmethyl)propan-1-one;(28)1-{5-[(8-cyclohexyl-2,8-diazaspiro[4.5]dec-2-yl)methyl]pyrimidin-2-yl}-3-(1H-imidazol-2-yl)-2-(1H-imidazol-2-ylmethyl)propan-1-one;(29)1-{5-[(8-cyclohexyl-2,8-diazaspiro[4.5]dec-2-yl)methyl]pyridin-2-yl}-3-(1H-imidazol-2-yl)-2-(1H-imidazol-2-ylmethyl)propan-1-one;(30)3-(1H-imidazol-2-yl)-2-(1H-imidazol-2-ylmethyl)-1-(4-{[8-(2-thienylmethyl)-2,8-diazaspiro[4.5]dec-2-yl]methyl}phenyl)propan-1-one;(31)3-(1H-imidazol-2-yl)-2-(1H-imidazol-2-ylmethyl)-1-(4-{[2-(2-thienylmethyl)-2,8-diazaspiro[4.5]dec-8-yl]methyl}phenyl)propan-1-one;(32)1-{4-[(2-cyclohexyl-2,8-diazaspiro[4.5]dec-8-yl)methyl]phenyl}-3-(1H-imidazol-2-yl)-2-(1H-imidazol-2-ylmethyl)propan-1-one;(33)1-{4-[(9-cyclohexyl-3,9-diazaspiro[5.5]undec-3-yl)methyl]phenyl}-3-(1H-imidazol-2-yl)-2-(1H-imidazol-2-ylmethyl)propan-1-one;(34)1-{4-[(9-cyclohexyl-2,9-diazaspiro[5.5]undec-2-yl)methyl]phenyl}-3-(1H-imidazol-2-yl)-2-(1H-imidazol-2-ylmethyl)propan-1-one;(35)1-{4-[(8-cyclohexyl-2,8-diazaspiro[5.5]undec-2-yl)methyl]phenyl}-3-(1H-imidazol-2-yl)-2-(1H-imidazol-2-ylmethyl)propan-1-one;(36)1-{4-[(7-cyclohexyl-2,7-diazaspiro[4.4]non-2-yl)methyl]phenyl}-3-(1H-imidazol-2-yl)-2-(1H-imidazol-2-ylmethyl)propan-1-one;(37)1-{5-[(8-cyclohexyl-2,8-diazaspiro[4.5]dec-2-yl)methyl]-1,3-oxazol-2-yl}-3-(1H-imidazol-2-yl)-2-(1H-imidazol-2-ylmethyl)propan-1-one;(38)8-cyclohexyl-2-{4-[2-(1H-imidazol-2-yl)-1-(1H-imidazol-2-ylmethyl)ethyl]benzyl}-2,8-diazaspiro[4.5]decane;(39)8-cyclohexyl-2-({4-[2-(1H-imidazol-2-yl)-1-(1H-imidazol-2-ylmethyl)ethyl]cyclohexyl}methyl)-2,8-diazaspiro[4.5]decane;(40)8-cyclohexyl-2-({1-[2-(1H-imidazol-2-yl)-1-(1H-imidazol-2-ylmethyl)ethyl]piperidin-4-yl}methyl)-2,8-diazaspiro[4.5]decane;(41)8-cyclohexyl-2-[7-(1H-imidazol-2-yl)-6-(1H-imidazol-2-ylmethyl)heptyl]-2,8-diazaspiro[4.5]decane;(42)4-(8-cyclohexyl-2,8-diazaspiro[4.5]dec-2-yl)-N-[2-(1H-imidazol-2-yl)-1-(1H-imidazol-2-ylmethyl)ethyl]butan-1-amine;(43)7-(8-cyclohexyl-2,8-diazaspiro[4.5]dec-2-yl)-1-(1H-imidazol-2-yl)-2-(1H-imidazol-2-ylmethyl)heptan-3-ol;(44)7-(8-cyclohexyl-2,8-diazaspiro[4.5]dec-2-yl)-1-(1H-imidazol-2-yl)-2-(1H-imidazol-2-ylmethyl)heptan-3-one;(45)1-[4-({[4-(dipropylamino)butyl]amino}methyl)phenyl]-3-pyridin-2-yl-2-(pyridin-2-ylmethyl)propan-1-one;(46)1-[4-({[4-(dipropylamino)butyl]amino}methyl)phenyl]-3-(1H-imidazol-2-yl)-2-(1H-imidazol-2-ylmethyl)-2-methylpropan-1-one;(47)N-[3-(8-cyclohexyl-2,8-diazaspiro[4.5]dec-2-yl)propyl]-3-(1H-imidazol-2-yl)-2-(1H-imidazol-2-ylmethyl)propanamide;(48)8-cyclohexyl-2-{3-[3-(1H-imidazol-2-yl)-2-(1H-imidazol-2-ylmethyl)propoxy]propyl}-2,8-diazaspiro[4.5]decane;(49)N-[3-(8-cyclohexyl-2,8-diazaspiro[4.5]dec-2-yl)propyl]-3-(1H-imidazol-2-yl)-2-(1H-imidazol-2-ylmethyl)propan-1-amine;(50)1-{4-[(8-cyclohexyl-2,8-diazaspiro[4.5]dec-2-yl)methyl]phenyl}-3-(1H-imidazol-2-yl)-2-(1H-imidazol-2-ylmethyl)-2-methylpropan-1-one,salts thereof, N-oxides thereof or solvates thereof or prodrugs thereof.

Examples of more preferable compound include compounds described inExamples, salts thereof, N-oxides thereof or solvates thereof orprodrugs thereof.

Examples of particularly preferable compound include2-{4-[3-(1H-imidazol-2-yl)-2-(1H-imidazol-2-ylmethyl)propoxy]benzyl}-8-[(3-methyl-2-thienyl)methyl]-2,8-diazaspiro[4.5]decane,N-[3-(1H-imidazol-2-yl)-2-(1H-imidazol-2-ylmethyl)propyl]-N-[4-({8-[(3-methyl-2-thienyl)methyl]-2,8-diazaspiro[4.5]dec-2-yl}methyl)benzyl]acetamide,8-cyclohexyl-2-{4-[3-(1H-imidazol-2-yl)-2-(1H-imidazol-2-ylmethyl)propyl]benzyl}-2,8-diazaspiro[4.5]decane,3-({4-[(8-cyclohexyl-2,8-diazaspiro[4.5]dec-2-yl)methyl]benzyl}amino)-2,2-bis(1H-imidazol-2-ylmethyl)-1-propanol,2-{{4-[(8-cyclohexyl-2,8-diazaspiro[4.5]dec-2-yl)methyl]benzyl}[3-(1H-imidazol-2-yl)-2-(1H-imidazol-2-ylmethyl)propyl]amino}ethanol,N-[2-cyano-3-(1H-imidazol-2-yl)-2-(1H-imidazol-2-ylmethyl)propyl]-N-{4-[(8-cyclohexyl-2,8-diazaspiro[4.5]dec-2-yl)methyl]benzyl}acetamide,N-[3-(1H-imidazol-2-yl)-2-(1H-imidazol-2-ylmethyl)propyl]-4-[(8-isobutyl-2,8-diazaspiro[4.5]dec-2-yl)methyl]benzamide,N-[3-(1H-imidazol-2-yl)-2-(1H-imidazol-2-ylmethyl)propyl]-4-[(8-isobutyl-2,8-diazaspiro[4.5]dec-2-yl)methyl]-N-(2-methoxyethyl)benzamide,N-[3-(1H-imidazol-2-yl)-2-(1H-imidazol-2-ylmethyl)propyl]-4-[(8-isobutyl-2,8-diazaspiro[4.5]dec-2-yl)methyl]-N-[2-(-pyrrolidinyl)ethyl]benzamide,2-hydroxy-N-[3-(1H-imidazol-2-yl)-2-(1H-imidazol-2-ylmethyl)propyl]-N-{4-[(8-isobutyl-2,8-diazaspiro[4.5]dec-2-yl)methyl]benzyl}acetamide,N-[3-hydroxy-2,2-bis(1H-imidazol-2-ylmethyl)propyl]-N-{4-[(8-isobutyl-2,8-diazaspiro[4.5]dec-2-yl)methyl]benzyl}acetamide,N-[2-(dimethylamino)ethyl]-N-[3-(1H-imidazol-2-yl)-2-(1H-imidazol-2-ylmethyl)propyl]-4-[(8-isobutyl-2,8-diazaspiro[4.5]dec-2-yl)methyl]benzamide,N-(2-acetamidoethyl)-N-[3-(1H-imidazol-2-yl)-2-(1H-imidazol-2-ylmethyl)propyl]-4-[(8-isobutyl-2,8-diazaspiro[4.5]dec-2-yl)methyl]benzamide,N-[3-(1H-imidazol-2-yl)-2-(1H-imidazol-2-ylmethyl)propyl]-4-[(8-isobutyl-2,8-diazaspiro[4.5]dec-2-yl)methyl]-N-[2-(4-morpholinyl)ethyl]benzamide,3-({4-[(8-cyclohexyl-2,8-diazaspiro[4.5]dec-2-yl)methyl]benzoyl}amino)-2,2-bis(1H-imidazol-2-ylmethyl)propylacetate, salts thereof, N-oxides thereof or solvates thereof or prodrugsthereof.

[Method for Producing Compound of the Present Invention]

The compound of the present invention represented by formula (I) can beprepared by appropriately improving a known method, for example, methodsshown below, methods described in Examples, and a method described inComprehensive Organic Transformations: A Guide to Functional GroupPreparations, Second edition (written by Richard C. Larock, John Wiley &Sons Inc, 1999) and using improved methods in combination. In thefollowing production methods, starting compounds may be used in the formof a salt. As the salt, those described as a salt of the above describedformula (I) are used.

Among compounds represented by formula (I) of the present invention, acompound in which G represents G^(A) and G^(A) represents a carbon atomsubstituted with an oxo group, namely, a compound represented by formula(I-A):

wherein all symbols are as defined above can be produced by subjecting acompound represented by formula (2):

wherein R¹⁰¹ and R¹⁰² represent a C1-8 alkyl group, and other symbolsare as defined above or formula (3):

wherein R¹⁰³ represents C1-8 alkyl group, and other symbols are asdefined above and a compound represented by formula (4):

M-E-L-J  (4)

wherein M represents a metal atom (lithium, magnesium, zinc, etc.), andother symbols are as defined above to a coupling reaction and optionallysubjecting to a deprotection reaction of a protective group and/or acleavage reaction from a resin.

This coupling reaction is known and includes, for example:

(a) a method using an organolithium reagent,(b) a method using a Grignard reagent, and(c) a method using an organozinc reagent.

These methods are specifically described below.

(a) The method using an organolithium reagent is performed, for example,by reacting an aryl halide or an alkyl halide with lithium in an organicsolvent (tetrahydrofuran, diethylether, etc.) at −78° C. to a refluxtemperature and reacting the obtained lithium reagent, i.e. formula (4)with a compound represented by formula (2) or formula (3) in a solvent(tetrahydrofuran, diethylether, etc.) at −78° C. to a refluxtemperature.(b) The method using a Grignard reagent is performed, for example, byreacting an aryl halide or an alkyl halide with magnesium in an organicsolvent (tetrahydrofuran, diethylether, etc.) at −78° C. to a refluxtemperature and reacting the resulting Grignard reagent, i.e. formula(4) with a compound represented by formula (2) or formula (3) in asolvent (tetrahydrofuran, diethylether, etc.) at −78° C. to a refluxtemperature.(c) The method using an organozinc reagent is performed, for example, byreacting an aryl halide or an alkyl halide with a zinc reagent (zinc,dimethylzinc, diethylzinc, etc.) in an organic solvent (tetrahydrofuran,diethylether, acetonitrile, dimethylformamide, etc.) at −78° C. to areflux temperature and reacting the resulting organozinc reagent, i.e.formula (4) with a compound represented by formula (3) in a solvent(tetrahydrofuran, diethylether, acetonitrile, dimethylformamide, etc.)at −78° C. to a reflux temperature.

Any of these reactions (a), (b) and (c) is preferably performed in aninert gas (argon, nitrogen, etc.) atmosphere under anhydrous conditions.

The C1-8 alkyl group” represented by R¹⁰¹, R¹⁰² and R¹⁰³ here has thesame meaning as in the “C1-8 alkyl group” exemplified as for the“aliphatic hydrocarbon group having 1 to 8 carbon atom(s)” in the“aliphatic hydrocarbon group”.

The deprotection reaction of a protective group can be carried out by aknown method, for example, a method described in Protective Groups inOrganic Synthesis (written by T. W. Greene, John Wiley & Sons Inc,1999). The protective group is not specifically limited as long as it isa group which is described in the above documents or other group thatcan be deprotected easily and selectively.

If the compound has a moiety to bind to a resin in the molecule and theresin is a polystyrene resin, the compound of the present invention canbe cleaved from the resin by the following method. The reaction forcleavage from the resin is known and can be carried out, for example, byreacting in an organic solvent (dichloromethane, 1,2-dichloroethane,toluene, etc.) at 0 to 100° C. using an acid (acetic acid,trifluoroacetic acid, hydrochloric acid, etc.).

If necessary, the procedure of converting into the objective salt may becarried out by a known method after this reaction.

Among the compounds represented by formula (I) of the present invention,a compound wherein G represents G^(A) and G^(A) represents —CH₂—,namely, a compound represented by formula (I-B):

wherein all symbols are as defined above can be produced by subjecting acompound represented by formula (I-A):

wherein all symbols are as defined above to a reductive reaction andoptionally subjecting to a deprotection reaction of a protective groupand/or a cleavage reaction from a resin.

This reductive reaction is known and includes, for example:

(a) a reduction with metal and a metal salt,(b) a reduction with a metal halide,(c) a reduction with a metal hydride complex, and(d) a reduction with hydrazine.

The methods are specifically described below.

(a) The method using metal and a metal salt is performed by reactingwith metal and a metal salt (lithium, zinc, copper, mercury and amixture thereof) in an organic solvent (tetrahydrofuran, diethylether,methanol, ammonia, water and a mixture thereof) at −78° C. to a refluxtemperature.(b) The method using a metal halide is performed by reacting with ametal halide (triethylsilane, trichlorosilane, diphenylsilane, etc.)with or without using an organic solvent (dichloromethane,1,2-dichloroethane, trifluoroacetic acid and a mixture thereof) in thepresence or absence of a base (triethylamine, tri-n-propylamine, etc.)at −78° C. to a reflux temperature.(c) The reaction using a metal hydride complex is performed by reactingwith a metal hydride complex (lithium aluminum hydride, lithium aluminumhydride-aluminum trichloride, lithium tri-tert-butoxyaluminum hydride,etc.) in an organic solvent (tetrahydrofuran, diethylether, 1,4-dioxane,etc.) at −78° C. to a reflux temperature.(d) The method using hydrazine is performed by reacting with hydrazinein a solvent (methanol, ethanol, ethylene glycol, etc.) in the presenceof a strong base (sodium methoxide, sodium ethoxide, sodium hydroxide,potassium hydroxide, etc.) at room temperature to a reflux temperature.Any of these reactions (a), (b), (c) and (d) is preferably performed inan inert gas (argon, nitrogen, etc.) atmosphere under anhydrousconditions. Also, the deprotection reaction of a protective group or thecleavage reaction from a resin can be performed by the same methoddescribed above.

Among the compounds represented by formula (I) of the present invention,a compound wherein G represents G^(A), G^(A) represents —NR¹⁰⁴- and Rrepresents a hydrogen atom, namely, a compound represented by formula(I-C):

wherein R¹⁰⁴ represents a C1-8 alkyl group, other symbols are as definedabove, provided that the “C1-8 alkyl group” here has the same meaning asin the “C1-8 alkyl group” among the “aliphatic hydrocarbon group having1 to 8 carbon atom(s)” in the “aliphatic hydrocarbon group”, and othersymbols are as defined above can be produced by reacting a compoundrepresented by formula (5):

wherein all symbols are as defined above and a compound represented byformula (6):

wherein all symbols are as defined above to a reductive aminationreaction and optionally subjecting to a deprotection reaction of aprotective group and/or a cleavage reaction from a resin. The “C1-8alkyl group” represented by R¹⁰⁴ here has the same meaning as in the“C1-8 alkyl group” exemplified as for the “aliphatic hydrocarbon grouphaving 1 to 8 carbon atom(s)” in the above described “aliphatichydrocarbon group”.

This reductive amination reaction is known and is preferably performedin an organic solvent (dichloromethane, 1,2-dichloroethane,dimethylformamide, methanol, ethanol, acetic acid and a mixture thereof)in the presence of a reducing agent (sodium triacetoxyborohydride,sodium cyanoborohydride, sodium borohydride, etc.) at a temperature of 0to 40° C. The reductive amination reaction is preferably performed in aninert gas (argon, nitrogen, etc.) atmosphere under anhydrous conditions.Also, a deprotection reaction of a protective group and/or a cleavagereaction from a resin can be performed by the same method as describedabove.

Among compounds represented by formula (I) of the present invention, acompound wherein A¹ and A² represents an imidazol-2-yl group, namely, acompound represented by formula (I-D):

wherein all symbols are as defined above can be produced by subjectingto a cyclization reaction using a compound represented by formula (7):

wherein all symbols are as defined above and[2,2-bis(methylox)ethyl]amine or [2,2-bis(ethyloxy)ethyl]amine andoptionally subjecting to a deprotection reaction of a protective groupand/or a cleavage reaction from a resin.

This cyclization reaction is known and can be performed, for example, byimproving the method described in Synthesis, 2001, (10), 1546-1550. Forexample, it is performed by reacting a nitrile compound in an organicsolvent (methanol, ethanol, etc.) in the presence of a base (sodiummethoxide, sodium ethoxide, etc.) at 0 to 40° C. and then reacting thesolution in the presence of acetal and a dehydrating agent (glacialacetic acid) at 40 to 150° C. Also, a deprotection reaction of aprotective group or a cleavage reaction from a resin can be performed bythe same method as described above.

Among compounds represented by formula (I) of the present invention, acompound wherein G represents G^(1A)-G^(2A)-G^(3A), G^(1A) is a carbonylgroup and G^(2A) is a nitrogen atom which may have a substituent,namely, a compound represented by formula (I-E):

wherein R¹⁰⁵ has the same meaning as in the “substituent” represented byG^(2A) in the “nitrogen atom which may have a substituent(s)” and othersymbols are as defined above can be produced by subjecting a compoundrepresented by formula (8):

wherein W represents a hydroxyl group or a chlorine atom, and othersymbols are as defined above and a compound represented by formula (9):

wherein all symbols are as defined above to an amidation reaction andoptionally subjecting to a deprotection reaction of a protective groupand/or a cleavage reaction from a resin.

This amidation reaction is known and examples thereof include:

(1) a method using an acyl halide,(2) a method using a mixed acid anhydride, and(3) a method using a condensing agent.

These methods are described in detail below.

(1) The method using an acyl halide is carried out, for example, byreacting carboxylic acid with an acid halogenating agent (oxalylchloride, thionyl chloride, etc.) in an organic solvent (chloroform,dichloromethane, diethylether, tetrahydrofuran, etc.) or in the absenceof the solvent at −20° C. to reflux temperature. Then the obtained acylhalide derivative may be with amine in the presence of a base (pyridine,triethylamine, N,N-dimethylaniline, 4-dimethylaminopyridine,diisopropylethylamine, etc.) in an organic solvent (chloroform,dichloromethane, diethylether, tetrahydrofuran, etc.) at 0 to 40° C.Alternatively, the obtained acyl halide can be reacted with amine in anorganic solvent (dioxane, tetrahydrofuran, etc.) at 0 to 40° C. using anaqueous alkali solution (sodium bicarbonate water or sodium hydroxidesolution, etc.).(2) The method using a mixed acid anhydride is carried out, for example,by reacting carboxylic acid with an acyl halide (pivaloyl chloride,tosyl chloride, mesyl chloride, etc.) or an acid derivative (ethylchloroformate, butyl chloroformate, etc.) in the presence of a base(pyridine, triethylamine, N,N-dimethylaniline, 4-dimethylaminopyridine,diisopropylethylamine, etc.) in an organic solvent (chloroform,dichloromethane, diethylether, tetrahydrofuran, etc.) or in the absenceof the solvent at 0 to 40° C., and reacting the resulting mixed acidanhydride with amine in an organic solvent (chloroform, dichloromethane,diethylether, tetrahydrofuran, etc.) at 0 to 40° C.(3) The method using a condensing agent is carried out, for example, byreacting carboxylic acid with amine in an organic solvent (chloroform,dichloromethane, dimethyl formamide, diethylether, tetrahydrofuran,etc.) or in the absence of the solvent at 0 to 40° C. in the presence orabsence of a base (pyridine, triethylamine, diisopropylethylamine,N,N-dimethylaniline, N-methylmorpholine, 4-dimethylaminopyridine, etc.),using a condensing agent (1,3-dicyclohexylcarbodiimide (DCC),1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide (EDC),1,1′-carbonyldiimidazole (CDI),O-(7-azabenzotriazol-1-yl)N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU), 2-chloro-1-methylpyridiniumiodine,1-propylphosphonic acid cyclic anhydride (1-propanephosphonic acidcyclic anhydride, PPA), etc.) and using, or not using,1-hydroxybenztriazole (HOBt) or 1-hydroxy-7-azabenzotriazole (HOAt).

The reactions described in (1), (2) and (3) are preferably carried outunder an inert gas (argon, nitrogen, etc.) atmosphere on anhydrouscondition.

The deprotection reaction of a protective group can be carried out bythe same method as described above.

Among the compounds represented by formula (I) of the present invention,a compound wherein G represents G^(1A)-G^(2A)-G^(3A), G^(2A) is anitrogen atom which may have a substituent and G^(3A) is a carbonylgroup, namely, a compound represented by formula (I-F):

wherein all symbols are as defined above can be produced by subjecting acompound represented by formula (10):

wherein all symbols are as defined above and a compound represented byformula (11):

wherein all symbols are as defined above to an amidation reaction andoptionally subjecting to a deprotection reaction of a protective groupand/or a cleavage reaction from a resin.

The amidation reaction and the deprotection reaction of a protectivegroup can be carried out by the same method as described above.

Among the compounds represented by formula (I) of the present invention,a compound wherein L is a methylene group and J is2,8-diazaspiro[4.5]decane substituted with R¹, namely, a compoundrepresented by formula (I-G):

wherein all symbols are as defined above can be produced by subjecting acompound represented by formula (12):

wherein all symbols are as defined above and a compound represented byformula (13):

wherein all symbols are as defined above to a reductive aminationreaction and optionally subjecting to a deprotection reaction of aprotective group and/or a cleavage reaction from a resin.

The amidation reaction and the deprotection reaction of a protectivegroup can be carried out by the same method as described above.

Among the compound of the present invention represented by formula (I),a compound wherein G is G^(1A)-G^(2A)-G^(3A), both G^(1A) and G^(2A) area methylene group, and G^(2A) is a nitrogen atom which may have asubstituent, namely, a compound represented by formula (I-H):

can be prepared by subjecting a compound represented by formula (14):

wherein all symbols are as defined above, and a compound represented byformula (15):

wherein all symbols are as defined above, to the reductive aminationreaction, and if necessary to the deprotection reaction of a protectivegroup and/or the cleavage reaction from the resin, or by subjecting acompound represented by formula (16):

wherein all symbols are as defined above, and a compound represented byformula (17):

wherein all symbols are as defined above, to the reductive aminationreaction, and if necessary to the deprotection reaction of a protectivegroup and/or the cleavage reaction from the resin.

The reductive amination reaction, the deprotection reaction of aprotective group, or the cleavage reaction from the resin can be carriedout by the same method as described above.

The compounds represented by formulae (2) to (17) used as other startingmaterials or reagents can be easily prepared by using per se knownmethods or known methods, for example, methods described inComprehensive Organic Transformations: A Guide to Functional GroupPreparations, Second edition (written by Richard C. Larock, John Wiley &Sons Inc, 1999) in combination.

In the respective reactions in the present specification, as is apparentto those skilled in the art, the reaction with heating can be carriedout using a water bath, an oil bath, a sand bath, or microwave.

In the respective reactions in the present specification, a solid phasesupported reagent obtained by supporting on a polymer (for example,polystyrene, polyacrylamide, polypropylene, polyethylene glycol, etc.)may be used.

In the respective reactions in the present specification, the reactionproduct can be purified by conventional purification means, for example,distillation under normal pressure or reduced pressure, high performanceliquid chromatography using a silica gel or magnesium silicate, thinlayer chromatography, ion-exchange resin, scavenger resin orchromatography or washing, or recrystallization. The purification may becarried out for every reaction, or may be carried out after thecompletion of some reactions.

In the reaction using a polystyrene resin in the present specification,the reaction product can be purified by conventional purificationmethods, for example, washing plural times with a solvent (N,N-dimethylformamide, dichloromethane, methanol, tetrahydrofuran, toluene, aceticacid/toluene, etc.).

[Toxicity]

The compound of the present invention has very low toxicity and isconsidered to be safe enough for pharmaceutical use.

[Application to Pharmaceuticals]

The compound of the present invention has CXCR4 antagonistic activity inan animal including human, particularly human, and is thereforeeffective, for example, for a preventive and/or therapeutic agent forinflammatory and immune diseases, allergic diseases, infections,particularly HIV infection, and diseases associated with the infection,psychoneurotic diseases, cerebral diseases, cardiovascular diseases,metabolic diseases, and cancerous diseases. Also, the compound is usefulas an agent for regeneration therapy for the purpose of in vitro or invivo amplification of stem cells for gene therapy as well as peripheralblood stem cells mobilization and tissue repair. The compound isparticularly useful as an agent for transplantation medical treatmentused in organ transplantation including bone marrow transplantation,peripheral blood stem cell transplantation and tissue repair among inthe regeneration therapy. Furthermore, the compound is useful as anantiangiogenic agent that is effective for prevention and/or treatmentof diseases associated with neoangiogenesis, such as retinopathy(diabetic retinopathy, aged macular degeneration, glaucoma, etc.) andcancer proliferation.

Examples of the inflammatory and immune disease include rheumatoidarthritis, arthritis, retinopathy, gout, replacement organ rejection,graft-versus-host disease (GVHD), nephritis, psoriasis, rhinitis,conjunctivitis, multiple sclerosis, ulcerative colitis, Crohn's disease,shock associated with bacterial infection, pulmonary fibrosis, systemicinflammatory response syndrome (SIRS), acute lung injury, diabetes andthe like.

Examples of the allergic disease include asthma, atopic dermatitis,rhinitis, conjunctivitis and the like.

Examples of the disease associated with infection, particularly HIVinfection, include acquired immunodeficiency syndrome (AIDS),candidiasis, Pneumocystis carinii pneumonia, Cytomegalovirus retinitis,Kaposi's sarcoma, malignant lymphoma, AIDS encephalopathy, bacterialsepsis and the like.

Examples of the psychoneurotic disease and cerebral disease includedementia including Alzheimer's disease, Parkinson's disease, stroke,cerebral infarction, cerebral hemorrhage, epilepsia, schizophrenia,peripheral nerve disorder and the like.

Examples of the cardiovascular disease include arteriosclerosis,ischemia reperfusion, hypertension, myocardial infarction, stenocardia,heart failure and the like.

Examples of the metabolic diseases include diabetes, osteoporosis,enlarged prostate, frequent micturition and the like.

Examples of the cancerous disease include malignant tumor such as breastcancer or malignant lymphoma, cancer metastasis, myelosuppression orthrombocytopenia after radiation therapy/chemotherapy and the like.

The compound of the present invention may be administered as aconcomitant drug by using in combination with other drugs for thepurpose of:

1) complementation and/or enhancement of the preventive and/ortherapeutic effects of the compound,2) improvement of pharmacokinetics and absorption of the compound andreduction of the dosage, and/or3) reduction of side effects of the compound.

Also, other drugs may be administered as a concomitant drug by using incombination with the compound of the present invention the purpose of(1) complementation and/or enhancement of preventive and/or therapeuticeffects, (2) improvement of pharmacokinetics and absorption of thecompound and reduction of the dosage, and/or (3) reduction of sideeffects.

The concomitant drug of the compound of the present invention and otherdrugs may be administered in the form of a compounding agent(s)comprising both these components, or may be in the form of separately.In case of separately administering a preparation, simultaneousadministration and administration with time-lag are included. In case ofadministration with time-lag, other drugs may be administered after thecompound of the present invention is administered, or the compound ofthe present invention may be administered after other drugs may beadministered. The administration method may be the same or different.

The disease, on which the preventive and/or therapeutic effects areexerted by the concomitant drug, is not specifically limited, and may beany disease which complements and/or enhances the preventive and/ortherapeutic effects of the compound of the present invention.

A mass ratio of the compound of the present invention drug to otherdrugs is not specifically limited.

A combination of any two or more kinds other drugs may be administered.

The other drugs, which complements and/or enhances the preventive and/ortherapeutic effects of the compound of the present invention, includesnot only those which have ever been found based on the above describedmechanism, but also those which may be found in future.

Examples of the preventive and/or therapeutic agents for HIV infectionand acquired immunodeficiency syndrome, which is used in combination ofthe compound of the present invention, include reverse transcriptaseinhibitors, protease inhibitors, chemokine (for example, CCR2, CCR3,CCR4, CCR5, CXCR4, etc.) antagonists, CD4 antagonists, antibody againstsurface antigen of HIV (for example, HIV-1, HIV-2, etc.), vaccine of HIV(for example, HIV-1, HIV-2, etc.), short-interfering RNAs targeting aHIV-related factor and the like.

Examples of the reverse transcriptase inhibitors include (1) nucleosidereverse transcriptase inhibitors such as zidovudine (trade name:Retrovir), didanosine (trade name: Videx), zalcitabine (trade name:Hivid), stavudine (trade name: Zerit), lamivudine (trade name: Epivir),abacavir (trade name: Ziagen), didanosine (trade name: videx), adefovir,dipivoxil, emtricitabine (trade name: coviracil), tenofovir (trade name:viread), Combivir, Trizivir, truvada, epzicom, and the like, (2)non-nucleoside reverse transcriptase inhibitors such as nevirapine(trade name: viramune), delavirdine (trade name: Rescriptor), efavirenz(trade name: Sustiva, Stocrin), capravirine (AG1549), and the like.

Examples of the protease inhibitors include indinavir (trade name:Kurikisiban), ritonavir (trade name: norvir), nelfinavir (trade name:Viracept), saquinavir (trade name: Invirase, Fortovase), amprenavir(trade name: agenerase), lopinavir (trade name: Kaletra), atazanavir(trade name: Reyataz), fosamprenavir (trade name: lexiva), tipranavirand the like.

Examples of the chemokine antagonists include endogenous ligands of achemokine receptor, or derivatives and nonpeptidic low molecularcompounds thereof, an antibody against a chemokine receptor and thelike.

Examples of the endogenous ligands of the chemokine receptor includeMIP-1α, MIP-1β, RANTES, SDF-1α, SDF-1β, MCP-1, MCP-2, MCP-4, eotaxin,MDC and the like.

Examples of the derivative of the endogenous ligands include AOP-RANTES,Met-SDF-1α, Met-SDF-1β and the like.

Examples of the antibody of the chemokine receptor include Pro-140 andthe like.

Examples of the CCR2 antagonists include compounds described inWO99/07351, WO99/40913, WO00/46195, WO00/46196, WO00/46197, WO00/46198,WO00/46199, WO00/69432, WO00/69815, and Bioorg. Med. Chem. Lett., 10,1803 (2000), and the like.

Examples of the CCR3 antagonists include compounds described inDE19837386, WO99/55324, WO99/55330, WO00/04003, WO00/27800, WO00/27835,WO00/27843, WO00/29377, WO00/31032, WO00/31033, WO00/34278, WO00/35449,WO00/35451, WO00/35452, WO00/35453, WO00/35454, WO00/35876, WO00/35877,WO00/41685, WO00/51607, WO00/51608, WO00/51609, WO00/51610, WO00/53172,WO00/53600, WO00/58305, WO00/59497, WO00/59498, WO00/59502, WO00/59503,WO00/62814, WO00/73327, and WO01/09088, and the like.

Examples of the CCR4 antagonists include compounds described inWO02/030357 and WO02/030358, and the like.

Examples of the CCR5 antagonists include compounds described inWO99/17773, WO99/32100, WO00/06085, WO00/06146, WO00/10965, WO00/06153,WO00/21916, WO00/37455, EP1013276, WO00/38680, WO00/39125, WO00/40239,WO00/42045, WO00/53175, WO00/42852, WO00/66551, WO00/66558, WO00/66559,WO00/66141, WO00/68203, JP2000-309598, WO00/51607, WO00/51608,WO00/51609, WO00/51610, WO00/56729, WO00/59497, WO00/59498, WO00/59502,WO00/59503, WO00/76933, WO98/25605, WO99/04794, WO99/38514 and Bioorg.Med. Chem. Lett., 10, 1803 (2000), TAK-779, SCH-351125 (SCH-C),SCH-417690 (SCH-D), UK-427857, GW 873140A (ONO-4128), TAK-220, TAK-652,and the like.

Examples of the CXCR4 antagonists include AMD-3100, AMD-070, T-22,KRH-1120, KRH-1636, KRH-2731, CS-3955, and compounds described inWO00/66112, WO2004/024697, WO2004/052862, EP01493438, JP2002-371042,JP2004-196769, US2004/0132642, US2005/0192272, US2005/0215543,US2005/0215544, US2005/0215545, WO99/36091, WO02/094261, WO02/096397,WO03/029218, WO03079020, WO2004/020462, WO2004/024178, WO2004/024697,WO2004/054603, WO2004/059285, WO2004/087068, WO2004/093817,WO2004/096838, WO2004/096839, WO2004/096840, WO2005/002522,WO2005/002551, WO2005/025565, WO2005/085209, WO2005/085219,WO2006/020415, WO2006/022454, WO2006/023400, WO2006/039252, and thelike.

Examples of the fusion inhibitors include T-20 (pentafuside) T-1249, andthe like.

Examples of the HIV integrase inhibitors include Equisetin, Temacrazine,PL-2500, V-165, NSC-618929, L-870810, L-708906 analog, S-1360, 1838 andthe like.

The Short Interfering short-interfering RNAs targeting a HIV-relatedfactor include those which target a gene of a HIV-related factor.Examples of the HIV-related factors include reverse transcriptase,protease, chemokine (CCR2, CCR3, CCR4, CCR5, CXCR4, etc.), CD4, HIV(HIV1, HIV2, etc.) and the like.

The conventional clinical dosage of typical reverse transcriptaseinhibitors and protease inhibitors is, for example, as described below,but is not limited thereto in the present invention.

Zidovudine: 100 mg capsule, three times per day in a dosage of 200 mg;300 mg tablet, twice per day in a dosage of 300 mg;Didanosine: 25 to 200 mg tablet, twice per day in a dosage of 125 to 200mg;Zalcitabine: 0.375 mg to 0.75 mg tablet, three times per day in a dosageof 0.75 mg;Stavudine: 15 to 40 mg capsule, twice per day in a dosage of 30 to 40mg;Lamivudine: 150 mg tablet, twice per day in a dosage of 150 mg;Abacavir: 300 mg tablet, twice per day in a dosage of 300 mg;Nevirapine: 200 mg tablet, once per day for 14 days in a dosage of 200mg, followed by twice per day;Delavirdine: 100 mg tablet, three times per day in a dosage of 400 mg;Efavirenz: 50 to 200 mg capsule, once per day in a dosage of 600 mg;Indinavir: 200 to 400 mg capsule, three times per day in a dosage of 800mg;Ritonavir: 100 mg capsule, twice per day in a dosage of 600 mg;Nelfinavir: 250 mg tablet, three times per day in a dosage of 750 mg;Saquinavir: 200 mg capsule, three times per day in a dosage of 1,200 mg;Amprenavir: 50 to 150 mg tablet, twice per day in a dosage of 1,200 mg.

Examples of the other drugs for complementation and/or enhancement ofthe preventive and/or therapeutic effects of the compound of the presentinvention against asthma include antihistaminic agents, antiallergicagents (chemical mediator release inhibitors, histamine antagonists,thromboxane synthetase inhibitors, thromboxane antagonists, Th2 cytokineinhibitors), steroids, bronchodilator agents (xanthine derivatives,sympathomimetic agents, parasympathomimetic agents), vaccinotherapeuticagents, gold preparations, Chinese medicines, basic nonsteroidalanti-inflammatory drugs, 5-lipoxygenase inhibitors, 5-lipoxygenaseactivation protein antagonists, leukotriene synthesis inhibitors,prostaglandins, cannabinoid-2 receptor stimulants, antitussive drugs,expectorants, and the like.

Examples of the antihistaminic agents include diphenhydramine,diphenylpyraline hydrochloride, diphenylpyraline chlorotheophyllinate,clemastine fumarate, dimenhydrinate, dl-chlorpheniramine maleate,d-chlorpheniramine maleate, triprolidine hydrochloride, promethazinehydrochloride, alimemazine tartrate, isothipendyl hydrochloride,homochlorcyclizine hydrochloride, hydroxyzine, cyproheptadinehydrochloride, levocabastine hydrochloride, astemizole, bepotastine,desloratadine, TAK-427, ZCR-2060, NIP-530, mometasone furoate,mizolastine, BP-294, andolast, auranofin, acrivastine and the like.

Examples of the chemical mediator release inhibitors include disodiumcromoglycate, tranilast, amlexanox, repirinast, ibudilast, pemirolastpotassium, tazanolast, nedocromil, cromoglicate, israpafant and thelike.

Examples of the histamine antagonists include ketotifen fumarate,azelastine hydrochloride, oxatomide, mequitazine, terfenadine,emedastine fumarate, epinastine hydrochloride, ebastine, cetirizinehydrochloride, olopatadine hydrochloride, loratadine, fexofenadine andthe like.

Examples of the thromboxane synthetase inhibitors include ozagrelhydrochloride imitrodast sodium and the like.

Examples of the thromboxane antagonists include seratrodast, ramatroban,domitroban calcium hydrate, KT-2-962 and the like.

Examples of the Th2 cytokine inhibitors include suplatast tosilate andthe like.

Examples of the steroids include, for example, external medicine such asclobetasol propionate, diflorasone diacetate, fluocinonide, mometasonefuroate, betamethasone dipropionate, betamethasone butyrate propionate,betamethasone valerate, difluprednate, budesonide, diflucortolonevalerate, amcinonide, halcinonide, dexamethasone, dexamethasonepropionate, dexamethasone valerate, dexamethasone acetate,hydrocortisone acetate, hydrocortisone butyrate, hydrocortisone butyratepropionate, deprodone propionate, prednisolone valerate acetate,fluocinolone acetonide, beclometasone dipropionate, triamcinoloneacetonide, flumetasone pivalate, alclometasone propionate, clobetasonebutyrate, prednisolone, beclomethasone propionate, fludroxycortide, andthe like; internal use and injections such as cortisone acetate,hydrocortisone, hydrocortisone sodium phosphate, hydrocortisone sodiumsuccinate, fludrocortisone acetate, prednisolone, prednisolone acetate,prednisolone sodium succinate, prednisolone butylacetate, prednisolonesodium phosphate, halopredone acetate, methyl prednisolone,methylprednisolone acetate, methylprednisolone sodium succinate,triamcinolone, triamcinolone acetate, triamcinolone acetonide,dexamethasone, dexamethasone acetate, dexamethasone sodium phosphate,dexamethasone palmitate, paramethasone acetate, betamethasone and thelike; and inhalations such as beclometasone dipropionate, fluticasonepropionate, budesonide, flunisolide, triamcinolone, ST-126P,ciclesonide, dexamethasone palmitate, mometasone furoate, prasteronesulfonate, deflazacort, methylprednisolone suleptanate,methylprednisolone sodium succinate and the like.

Examples of the xanthine derivative include aminophylline, theophylline,doxophylline, cipamfylline, diprophylline, proxyphylline, and cholinetheophylline.

Examples of the sympathomimetic agents include epinephrine, ephedrinehydrochloride, dl-methylephedrine hydrochloride, methoxyphenaminehydrochloride, isoproterenol sulfate, isoproterenol hydrochloride,orciprenaline sulfate, chloroprenaline hydrochloride, trimetoquinolhydrochloride, salbutamol sulfate, terbutaline sulfate, hexoprenalinesulfate, tulobuterol hydrochloride, procaterol hydrochloride, fenoterolhydrobromate, formoterol fumarate, clenbuterol hydrochloride, mabuterolhydrochloride, salmeterol xinafoate, R,R-formoterol, tulobuterol,pirbuterol hydrochloride, ritodrine hydrochloride, bambuterol,dopexamine hydrochloride, meluadrine tartrate, AR-C68397,levosalbutamol, KU R-1246, KUL-7211, AR-C89855, S-1319 and the like.

Examples of the parasympathomimetic agents include ipratropium bromide,flutropium bromide, oxitropium bromide, cimetropium bromide, temiverine,tiotropium bromide, revatropate (UK-112166) and the like.

Examples of the vaccinotherapeutic agents include paspat, asthremedin,Broncasma Berna, CS-560 and the like.

Examples of the gold preparations include gold sodium thiomalate and thelike.

Examples of the basic nonsteroidal anti-inflammatory drugs includetiaramide hydrochloride, tinoridine hydrochloride, epirizole, emorfazoneand the like.

Examples of the 5-lipoxygenase inhibitors include zyleuton, docebenone,piriprost, SCH-40120, WY-50295, E-6700, ML-3000, TMK-688, ZD-2138,dalbufelone mesilate, R-68151, E-6080, DuP-654, SC-45662, CV-6504,NE-11740, CMI-977, NC-2000, E-3040, PD-136095, CMI-392, TZI-41078,Orf-20485, IDB-18024, BF-389, A-78773, TA-270, FLM-5011, CGS-23885,A-79175, ETH-615 and the like.

Examples of the 5-lipoxygenase activation protein antagonists includeMK-591, MK-886 and the like.

Examples of the leukotriene synthesis inhibitors include auranofin,proglumetacin maleate, L-674636, A-81834, UPA-780, A-93178, MK-886,REV-5901A, SCH-40120, MK-591, Bay-x-1005, Bay-y-1015, DTI-0026,Amlexanox, E-6700 and the like.

Examples of the prostaglandins (hereinafter abbreviated to as PG)include PG receptor agonists, PG receptor antagonists and the like.

Examples of the PG receptor include PGE receptor (EP1, EP2, EP3, andEP4), PGD receptor (DP, CRTH2), PGF receptor (FP), PGI receptor (IP), TXreceptor (TP) and the like.

Examples of the antitussive drugs include codeine phosphate,dihydrocodeine phosphate, oxymetebanol, dextromethorphan hydrobromate,pentoxyverine citrate, dimemorfan phosphate, oxeladin citrate,cloperastine, benproperine phosphate, clofedanol hydrochloride,fominoben hydrochloride, noscapine, tipepidine hibenzate, eprazinonehydrochloride, plantago herb extract and the like.

Examples of the expectorants include foeniculated ammonia spirit, sodiumhydrogencarbonate, potassium iodide, bromhexine hydrochloride, cherrybark extract, carbocysteine, fudosteine, ambroxol hydrochloride,ambroxol hydrochloride sustained-release tablet, methylcysteinehydrochloride, acetylcysteine, L-ethylcysteine hydrochloride, tyloxapoland the like.

Examples of the other drugs for complementation and/or enhancement ofthe preventive and/or therapeutic effects against atopic dermatitis(urticaria, etc.) of the compound of the present invention includesteroids, non-steroid anti-inflammatory drug (NSAID), immune inhibitor,prostaglandins, antiallergic agent, mediator release inhibitor,antihistaminic agent, forskolin preparation, phosphodiesteraseinhibitor, and cannabinoid-2 receptor stimulant.

Examples of the other drugs for complementation and/or enhancement ofthe preventive and/or therapeutic effects against allergic diseases(allergic bronchopulmonary aspergillosis, allergic eoisinophilicgastroenteritis, etc.) of the compound of the present invention includeantiasthmatic drug, inhaled steriod drug, inhaled β2 stimulant,methylxanthine-based stimulant, antiallergic agent, anti-inflammatoryagent, anticholinergic agent, thromboxane antagonist, leukotrieneantagonist, LTD4 antagonist, PAF antagonist, phosphodiesteraseinhibitor, β2 agonist, steroid drug, mediator release inhibitor,eosinophile leukocytechemotaxis inhibitor, macrolide-based antibiotic,immune inhibitor, hyposensitization (allergen) injection and the like.

Examples of the antiasthmatic drug include theophylline, procaterol,ketotifen, azelastine and the like.

Examples of the inhaled steriod drug include beclomethasone,fluticasone, budesonide and the like.

Examples of the inhaled β2 stimulant include fenoterol, s albutamol,formoterol, salmeterol and the like.

Examples of the methylxanthine-based stimulant include theophylline andthe like.

Examples of the antiallergic agent include ketotifen, terfenadine,azelastine, epinastine, suplatast, disodium cromoglycate and the like.

Examples of the anti-inflammatory agent include dichlofenac sodium,ibuprofen, indomethacin and the like.

Examples of the anticholinergic agent include ipratropium bromide,flutropium bromide, oxitropium bromide, tiotropium bromide and the like.

Examples of the thromboxane antagonists include ozagrel hydrochlorideimitrodast sodium and the like.

Examples of the leukotriene antagonist include pranlukast, montelukast,zafirlukast, zyleuton and the like.

Examples of the macrolide-based antibiotic include erythromycin,roxithromycin and the like.

Examples of the immune inhibitor include cyclosporine, tacrolimus,FTY720, and the like.

Examples of the other drug for complementation and/or enhancement of thepreventive and/or therapeutic effects against hepatitis of the compoundof the present invention include liver hydrolysate preparation,polyenephosphatidylcholine, glycyrrhizin preparation, protoporphyrinsodium, ursodeoxycholic acid, steroids, anticholinergic agent, gastricantiacid, propagermanium, lipid peroxidase inhibitor, and mitochondrialbenzodiazepine receptor antagonist.

Examples of the other drug for complementation and/or enhancement of thepreventive and/or therapeutic effects against arthritis and rheumatoidarthritis of the compound of the present invention includemetalloproteinase inhibitor, immune inhibitor, non-steroidanti-inflammatory drug (NSAID), steroid drug, prostaglandins,phosphodiesterase inhibitor, cannabinoid-2 receptor stimulant, diseasemodifying anti-rheumatic drug (slow-acting anti-rheumatic drug),anti-inflammatory enzyme preparation, cartilage protective agent, T cellinhibitor, TNFα inhibitor, prostaglandin synthetase inhibitor, IL-6inhibitor, interferon γ agonist, IL-1 inhibitor and the like.

Examples of the other drug for complementation and/or enhancement of thepreventive and/or therapeutic effects against psoriasis of the compoundof the present invention include steroid drug, vitamin D derivative andthe like.

Examples of the other drug for complementation and/or enhancement of thepreventive and/or therapeutic effects against conjunctivitis of thecompound of the present invention include leukotriene receptorantagonist, antihistaminic agent, mediator release inhibitor,non-steroid anti-inflammatory drug, prostaglandins, steroid drug,nitrogen monoxide synthetase inhibitor, cannabinoid-2 receptor stimulantand the like.

Examples of the other drug for complementation and/or enhancement of thepreventive and/or therapeutic effects against multiple sclerosis of thecompound of the present invention include immune inhibitor,cannabinoid-2 receptor stimulant and the like.

Examples of the other drug for complementation and/or enhancement of thepreventive and/or therapeutic effects against multiple sclerosis of thecompound of the present invention include immune inhibitor,cannabinoid-2 receptor stimulant and the like.

Examples of the other drug for complementation and/or enhancement of thepreventive and/or therapeutic effects against ulcerative colitis of thecompound of the present invention include mesalazine,salazosulfapyridine, digestive tract ulcer therapeutic substance,anticholinergic agent, steroid drug, 5-lipoxygenase inhibitor,antioxidant, LTB4 antagonist, local anesthetic, immune inhibitor,protection factor enhancer, MMP inhibitor, and mitochondrialbenzodiazepine receptor antagonist.

Examples of the other drug for complementation and/or enhancement of thepreventive and/or therapeutic effects against diabetic complication ofthe compound of the present invention include sulfonyl urea-basedhypoglycemic agent, biguanide-based drug, α-glucosidase inhibitor,ultrashort-acting insulinotropic agent, insulin drug, PPAR agonist,insulin sensitive enhancer having no PPAR antagonism, β3 adrenalinreceptor agonist, aldose reductase inhibitor, dipeptidyl peptidase IVinhibitor and the like.

Examples of the sulfonyl urea-based hypoglycemic agent includeacetohexamide, glibenclamide, gliclazide, glyclopyramide,chlorpropamide, tolazamide, tolbutamide, Glimepiride and the like.

Examples of the biguanide-based drug include buformin hydrochloride,metformin hydrochloride and the like.

Examples of the α-glucosidase inhibitor include acarbose, voglibose andthe like.

Examples of the ultrashort-acting insulinotropic agent includenateglinide, repaglinide and the like.

Examples of the PPAR agonist include pioglitazone, troglitazone,rosiglitazone, JTT-501, and the like.

Examples of the insulin sensitive enhancer having no PPAR antagonisminclude ONO-5816, YM-440 and the like.

Examples of the β3 adrenalin receptor agonist include AJ9677, L750355,CP331648 and the like.

Examples of the aldose reductase inhibitor include epalrestat,fidarestat, zenarestat and the like.

Examples of the other drug for complementation and/or enhancement of thepreventive and/or therapeutic effects against cancer (malignant tumor)and cancer metastasis of the compound of the present invention includeanticancer agent (for example, MMP inhibitor, alkylation agent (forexample, cyclophosphamide, melphalan, thiotepa, mytomycin C, busulfan,procarbazine hydrochloride, etc.), antimetabolite (for example,methotrexate, mercaptpurine, azathiopurine, fluorouracil, tegafur,cytarabine, azaserine, etc.), antibiotic (for example, mytomycin C,bleomycin, Peplomycin, doxorubicin hydrochloride, aclarubicin,daunorubicin, actinomycin D, etc.), mitosis inhibitor, platinum complex(for example, Cisplatin), plant-derived antineoplastic agent (forexample, vincristine sulfate, vinblastine sulfate, etc.), anticanceroushormone (for example, methyltestosterone, testosterone propionate,testosterone enanthate, mepitiostane, fosfestrol, chlormadinone acetate,etc.), immunopotentiator (for example, picibanil, krestin, etc.), andinterferon (for example, IFNα, IFNα-2a, IFNα-2b, IFNβ, IFNγ-1a, etc.).Examples thereof include biologics capable of conducting T cellactivation (for example, anti-CTLA-4 antibody, anti-PD-1 antibody,etc.), antiangiogenic agent (for example, bevacizumab, pegaptanib,SU-6668, vatalanib, ranibizumab, sorafenib, SU-11248, neovastat), etc.),and the like.

Examples of the other drug for complementation and/or enhancement of thepreventive and/or therapeutic effects against immune disease (forexample, autoimmune disease, rejection of transplanted organ, etc.) ofthe compound of the present invention include immune inhibitor (forexample, cyclosporine, tacrolimus, FTY720, etc.) and the like.

Examples of the other drug for complementation and/or enhancement of thepreventive and/or therapeutic effects against dementia such as Seniledementia with Alzheimer's type of the compound of the present inventioninclude acetylcholine esterase inhibitor, nicotinic receptor modifier,cerebral ameliorator, monoamineoxidase inhibitor, vitamin E, aldosereductase inhibitor and the like.

Examples of the other drug for complementation and/or enhancement of thepreventive and/or therapeutic effects against epilepsia of the compoundof the present invention include phenyloin, trimethadione, ethosuximide,carbamazepine, phenobarbitone, primidone, acetazolamide, sultiame,sodium valproate, clonazepam, diazepam, nitrazepam and the like.

Examples of the other drug for complementation and/or enhancement of thepreventive and/or therapeutic effects against arteriosclerosis of thecompound of the present invention include HMG-COA reductase inhibitor,fibrates, probucol preparation, anion-exchange resin, EPA preparation,nicotinic acid preparation, MTP inhibitor, other anti-high cholesterolagent, EDG-2 antagonist and the like.

Examples of the other drug for complementation and/or enhancement of theeffects when the compound of the present invention is used in aregeneration therapy include cytokines and various growth factors, forexample, various CSFs (for example, G-CSF, GM-CSF, etc.), variousinterleukins (for example, IL-3, 6, 7, 11, 12, etc.), EPO, TPO, SCF,FLT3 ligand, MIP-1α and the like.

Examples of the other drug for complementation and/or enhancement of thepreventive and/or therapeutic effects against retinopathy of thecompound of the present invention include antiangiogenic agent (forexample, bevacizumab, pegaptanib, SU-6668, vatalanib, ranibizumab,sorafenib, SU-11248, neovastat, etc.) and the like.

The compound of the present invention is safe and has low toxicity andtherefore can be administered to human and mammal other than human (forexample, rat, mouse, rabbit, sheep, pig, cow, cat, dog, monkey, etc.).

In order to use a pharmaceutical composition comprising the compound ofthe present invention or a concomitant drug of the compound of thepresent invention and other drugs, it is commonly administered,systematically or locally, in an oral or parenteral dosage form.

The dosage of the pharmaceutical preparation varies depending on theage, body weight, symptom, the desired therapeutic effect, the route ofadministration and duration of treatment. For the human adult, thedosage per person is between 1 ng and 1000 mg, by oral administration,up to several times per day, between 0.1 ng and 100 mg, by parenteraladministration, or continuous administration 1 hour to 24 hours per dayfrom vein.

As mentioned above, the doses to be used depend upon various conditions.Therefore, there are cases in which doses lower than or greater than theranges specified above may be used.

In case of administering a pharmaceutical composition comprising thecompound of the present invention, or a concomitant drug of the compoundof the present invention and other drugs, it is used as solidpreparations for internal use and solutions for internal use for oraladministration, and injections, external preparations, suppositories,ophthalmic solutions, nasal drops, inhalants for parenteraladministration and the like.

Examples of the solid preparation for internal use for oraladministration include tablets, pills, capsules, powders, and granules.Capsules include hard capsules and soft capsules.

In such a solid preparation for internal use, one or more activesubstances are used as they are, or used after mixing with excipients(lactose, mannitol, glucose, microcrystalline cellulose, starch, etc.),binders (hydroxypropyl cellulose, polyvinyl pyrrolidone, magnesiumaluminometasilicate, etc.), disintegrants (calcium carboxymethylcellulose, etc.), lubricants (magnesium stearate, etc.), stabilizers andsolubilizing agents (glutamic acid, aspartic acid, etc.) and forminginto a preparation according to a conventional method. If necessary, thepreparation may be coated with a coating agent (saccharose, gelatin,hydroxypropyl cellulose, hydroxypropylmethyl cellulosephthalate, etc.)or may be coated with two or more layers. Furthermore, capsules made ofan absorbable substance such as gelatin is included.

The solutions for internal use for oral administration includepharmaceutically acceptable water, suspensions, emulsions, syrups, andelixirs. In such a solution, one or more active substances aredissolved, suspended or emulsified in a diluent used commonly (purifiedwater, ethanol, mixed solution thereof, etc.). Furthermore, thissolution may contain humectants, suspending agents, emulsifiers,sweeteners, flavors, aromatics, preservatives, buffers, and the like.

The dosage form of the external preparation for parenteraladministration includes, for example, ointment, gel, cream, fomentation,patch, liniment, propellant, inhalant, spray, aerosol, ophthalmicsolution, and nasal drop. These products contain one or more activesubstances and are prepared according to the formulation which is knownor commonly used.

An ointment is prepared in accordance with a well known formulation or acommonly employed formulation. For example, it is prepared bytriturating or dissolving one or more active substances in a base. Anointment base is selected from well known ones or those commonlyemployed. For example, those selected from higher fatty acids or higherfatty acid esters (adipic acid, myristic acid, palmitic acid, stearicacid, oleic acid, adipate ester, myristate ester, palmitate ester,stearate ester, oleate ester, etc.), waxes (beeswax, whale wax, ceresin,etc.), surfactants (polyoxyethylene alkyl ether phosphate ester, etc.),higher alcohols (cetanol, stearyl alcohol, cetostearyl alcohol, etc.),silicone oils (dimethylpolysiloxane, etc.), hydrocarbons (hydrophilicpetrolatum, white petrolatum, purified lanolin, liquid paraffin, etc.),glycols (ethylene glycol, diethylene glycol, propylene glycol,polyethylene glycol, macrogol, etc.), vegetable oils (castor oil, oliveoil, sesame oil, turpentine oil, etc.), animal oils (mink oil, egg yolkoil, squalane, squalene, etc.), water, absorption accelerators, agentsfor preventing contact dermatitis are used alone or in combination.Furthermore, it may contain humectants, preservatives, stabilizers,antioxidizing agents, flavors, and the like.

A gel is prepared according to the formulation which is known orcommonly used. For example, it is prepared by dissolving one or moreactive substances in a base. A gel base is selected from a base which isknown or commonly used. For example, those selected from lower alcohols(ethanol, isopropyl alcohol, etc.), gelling agents (carboxymethylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, ethylcellulose, etc.), neutralizers (triethanolamine, diisopropanolamine,etc.), surfactants (monostearic acid polyethylene glycol, etc.), gums,water, absorption accelerator, and agent for preventing contactdermatitis are used alone or in combination. Furthermore, it may containpreservatives, antioxidizing agents, flavoring agent and the like.

A cream is prepared according to the formulation which is known orcommonly used. For example, it is prepared by dissolving or emulsifyingone or more active substances in a base. A cream base is selected from abase which is known or commonly used. For example, those selected fromhigher fatty acid esters, lower alcohols, hydrocarbons, polyhydricalcohols (propylene glycol, 1,3-butylene glycol, etc.), higher alcohols(2-hexyl decanol, cetanol, etc.), emulsifiers (polyoxyethylene alkylethers, fatty acid esters, etc.), water, absorption accelerators, andagents for preventing contact dermatitis are used alone or incombination. Furthermore, it may contain preservatives, antioxidizingagents, flavoring agent and the like.

A fomentation is prepared according to the formulation which is known orcommonly used. For example, it is prepared by dissolving one or moreactive substances in a base to obtain a kneaded mixture and spreadingthe kneaded mixture over a substrate. A fomentation base is selectedfrom a base which is known or commonly used. For example, those selectedfrom thickeners (polyacrylic acid, polyvinyl pyrrolidone, gum arabic,starch, gelatin, methyl cellulose, etc.), humectants (urea, glycerin,propylene glycol, etc.), fillers (kaolin, zinc oxide, talc, calcium,magnesium, etc.), water, solubilizing agents, tackifiers, and agents forpreventing contact dermatitis are used alone or in combination.Furthermore, it may contain preservatives, antioxidizing agents,flavoring agent and the like.

A patch is prepared according to the formulation which is known orcommonly used. For example, it is prepared by dissolving one or moreactive substances in a base, and spreading the solution over asubstrate. A patch base is selected from a base which is known orcommonly used. For example, those selected from polymer bases, fats andoils, higher fatty acids, tackifiers, and agents for preventing contactdermatitis are used alone or in combination. Furthermore, it may containpreservatives, antioxidizing agents, flavoring agent and the like.

A liniment is prepared according to the formulation which is known orcommonly used. For example, it is prepared by dissolving, suspending oremulsifying one or more active substances in one or more kinds selectedfrom water, alcohol (ethanol, polyethylene glycol, etc.), higher fattyacid, glycerin, soap, emulsifier, and suspending agent. Furthermore, itmay contain preservatives, antioxidizing agents, flavoring agent and thelike.

A propellant, an inhalant, and a spray may contain, in addition to adiluent used commonly, a stabilizer such as sodium hydrogensulfite and abuffer capable of imparting isotonicity, for example, an isotonicitysuch as sodium chloride, sodium citrate or citric acid. The method forproducing a spray is described in detail in U.S. Pat. No. 2,868,691 andU.S. Pat. No. 3,095,355.

An injection for parenteral administration includes all injections andalso includes a drop. For example, it includes intramuscular injection,subcutaneous injection, endodermic injection, intraarterial injection,intravenous injection, intraperitoneal injection, intraspinal injection,and intravenous drop.

The injection for parenteral administration includes solutions,suspensions, emulsions, and solid injections used by dissolving orsuspending in a solvent before use. The injection is used afterdissolving, suspending, or emulsifying one or more active substances ina solvent. As the solvent, for example, distilled water for injection,physiological saline, vegetable oil, and alcohols such as propyleneglycol, polyethylene glycol or ethanol are used alone or in combination.Furthermore, the injection may contain stabilizers, solubilizing agents(glutamic acid, aspartic acid, polysolvate 80®, etc.), suspendingagents, emulsifiers, soothing agents, buffers, and preservatives. Theseinjections are prepared by sterilizing in the final process, or preparedby an aseptic treatment. Also, a sterile solid, for example, afreeze-dried product is prepared and can be used after dissolving insterilized distilled water or distilled water for sterile injection, orthe other solvent before use.

An ophthalmic solution for parenteral administration includes ophthalmicsolution, suspension type ophthalmic solution, emulsion type ophthalmicsolution, ophthalmic solution soluble when used, and eye ointment.

These ophthalmic solutions are prepared according to a known method. Forexample, one or more active substances are dissolved, suspended oremulsified in a solvent before use. As the solvent for ophthalmicsolution, for example, sterilized purified water, physiological saline,and other aqueous solvent or non-aqueous agent for injection (forexample, vegetable oil, etc.) are used alone or in combination. Ifnecessary, the ophthalmic solution may contain appropriately selectedisotonizing agents (sodium chloride, concentrated glycerin, etc.),buffering agents (sodium phosphate, sodium acetate, etc.), surfactants(polysolvate 80 (trade name), polyoxyl 40 stearate, polyoxyethylenehardened castor oil, etc.), stabilizers (sodium citrate, sodium edetate,etc.), and antiseptics (benzalkonium chloride, paraben, etc.) Theseophthalmic solutions are prepared by sterilizing in the final process,or prepared by an aseptic treatment. Also, a sterile solid, for example,a freeze-dried product is prepared and can be used after dissolving insterilized distilled water or distilled water for sterile injection, orthe other solvent before use.

An inhalant for parenteral administration includes aerozol, inhalationpowder, and inhalation solution, and the inhalation solution may be sucha configuration that it is used after dissolving in water or othersuitable medium at the point of use.

These inhalants are prepared according to a known method.

For example, an inhalation solution is prepared by appropriatelyselecting antiseptics (benzalkonium chloride, paraben, etc.), colorants,buffering agents (sodium phosphate, sodium acetate, etc.), isotonizingagents (sodium chloride, concentrated glycerin, etc.), thickeners(carboxyvinyl polymer, etc.), and absorption accelerator, if necessary.

An inhalation powder is prepared by appropriately selecting lubricants(stearic acid and a salt thereof, etc.), binders (starch, dextrin,etc.), excipients (lactose, cellulose, etc.), colorants, antiseptics(benzalkonium chloride, paraben, etc.), and absorption accelerator ifnecessary.

In case of administering the inhalation solution, a spraying apparatus(atomizer, nebulizer) is commonly used. In case of administering theinhalation powder, an inhalation administration apparatus for powder iscommonly used.

The other composition for parenteral administration includessuppositories for intrarectal injection and pessaries for vaginaladministration, which contain one or more active substances and areformulate by a conventional method.

Designation of the compound of the present invention is described below.

The compounds used in the present invention were commonly designatedusing a computer program ACD/Name Batch® (manufactured by AdvancedChemistry Development Inc.) which designates according to the regulationof IUPAC, or commonly designated according to IUPAC Nomenclature. Forexample, a compound wherein A¹ and A² represent an imidazol-2-yl group,B¹ and B² represent a methylene group, G represents a carbon atomsubstituted by a oxo group, E represents a 1,4-phenylene group, Lrepresents —CH₂—, and J represents:

wherein the arrow represent the point to bind to L;namely, a compound represented by the following formula:

is designated as3-(1H-imidazol-2-yl)-2-(1H-imidazol-2-ylmethyl)-1-[4-({8-[(3-methyl-2-thienyl)methyl]-2,8-diazaspiro[4.5]dec-2-yl}methyl)phenyl]propan-1-one.

Also, in the compound in which two hydrogen atoms bonded to twodifferent carbon atoms of cycloalkane are substituted, a substituent issometimes substituted on both faces formed by ring or a substituent issometimes substituted on the same side, and the former was named“trans-isomer” while the latter was named “cis-isomer”.

BEST MODE FOR CARRYING OUT THE INVENTION

The present invention is described in detail based on Examples, but thepresent invention is not limited thereto.

The point of separation by chromatography and the solvent in theparentheses shown in TLC indicate a dissolution medium or an eluentused, and the proportion indicates a volume ratio.

NMR is a measured value of ¹HNMR at 300 MHz and the solvent shown in theparentheses of NMR indicates a solvent used in the measurement.

EXAMPLE 1 1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazole

Under an argon atmosphere, a dimethylformamide (500 mL) suspension ofsodium hydride (60%, 18.9 g) was ice-cooled and then imidazole (30.9 g)was added so as to prevent an inner temperature from rising to 5° C. orhigher. The reaction solution was stirred at 0° C. for 45 minutes. Tothe reaction solution, 2-(trimethylsilyl)ethoxymethyl chloride (72.4 g)was added dropwise. The reaction solution was stirred at roomtemperature for 14 hours. To the reaction solution, ice water (200 mL)was added. The aqueous layer was extracted twice with a solution(n-hexane:ethyl acetate=1:1 (200 mL)). The combined organic layer waswashed with saturated sodium chloride solution and then dried overanhydrous magnesium sulfate. After removing anhydrous magnesium sulfateby filtration, the filtrate was concentrated to obtain the titlecompound (116 g) having the following physical properties.

TLC: Rf 0.50 (ethyl acetate:methanol=9:1);

NMR (CDCl₃): δ-0.05-0.05 (m, 9H), 0.90 (dd, J=9.3, 8.4 Hz, 2H), 3.48 (m,2H), 5.29 (s, 2H), 7.06 (m, 1H), 7.12 (m, 1H), 7.71. (m, 1H).

EXAMPLE 2(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl)methanol

To an anhydrous tetrahydrofuran (1,000 mL) solution of compound (115 g)produced in Example 1, a tetrahydrofuran solution (260 mL) of 2N lithiumdiisopropylamide was added at −78° C. under an argon atmosphere. Thereaction solution was stirred at −78° C. for 2 hours. To this solution,dimethylformamide (100 mL) was added. The reaction solution was stirredat 0° C. for 30 minutes. To the reaction solution, water (200 mL) wasadded. The reaction solution was concentrated under reduced pressure.The aqueous layer was extracted three times with ethyl acetate (200 mL).The combined organic layer was washed in turn with water (100 mL) andsaturated sodium chloride solution (100 mL), and then dried overanhydrous magnesium sulfate. After removing the anhydrous magnesiumsulfate by filtration, the filtrate was concentrated. The residue waspurified by silica gel chromatography (n-hexane:ethyl acetate=4:1→2:1)to obtain the title compound (24.5 g) having the following physicalproperties.

TLC: Rf 0.63 (ethyl acetate:methanol:28% aqueous ammonia=90:10:1);

NMR (CDCl₃): δ-0.10-0.05 (m, 9H), 0.92 (m, 2H), 3.53 (m, 2H), 4.72 (s,2H), 5.36 (s, 2H), 6.94 (m, 1H), 6.98 (m, 1H).

EXAMPLE 32-(chloromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazoleHydrochloride

To a dichloromethane (30 mL) solution of the compound (2.44 g) producedin Example 2, thionyl chloride (1.85 mL) was added at 0° C. under anargon atmosphere. The reaction solution was stirred at room temperaturefor 30 minutes. To the reaction solution, a solution (n-hexane:ethylacetate=1:1 (100 mL)) was added. The precipitated solid was collected byfiltration. The solid was dried under reduced pressure to obtain thetitle compound (2.42 g) having the following physical properties.

TLC: Rf 0.71 (ethyl acetate:methanol:28% aqueous ammonia=90:10:1);

NMR (CDCl₃): δ 0.00-0.08 (m, 9H), 0.98 (dd, J=8.4, 7.8 Hz, 2H), 3.62 (t,J=8.4 Hz, 2H), 5.20 (s, 2H), 5.57 (s, 2H), 7.29 (d, J=1.8 Hz, 1H), 7.38(d, J=1.8 Hz, 1H).

EXAMPLE 4 Diethylbis[(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl)methyl]malonate

To an anhydrous tetrahydrofuran (10 mL) solution of diethyl malonate(566 mg), an ethanol solution (6 mL) of 20% sodium methoxide and thecompound (2.20 g) produced in Example 3 were added in this order. Thereaction solution was stirred at room temperature for 15 hours. To thereaction solution, a saturated aqueous ammonium chloride solution (10mL) was added and the aqueous layer was extracted twice withdichloromethane (50 mL). The combined organic layer was washed withsaturated sodium chloride solution (20 mL) and then dried over anhydrousmagnesium sulfate. After removing the anhydrous magnesium sulfate byfiltration, the filtrate was concentrated. The residue was purified bysilica gel chromatography (n-hexane:ethyl acetate=3:1→1:1) to obtain thetitle compound (1.60 g) having the following physical properties.

TLC: Rf 0.21 (n-hexane:ethyl acetate=1:2);

NMR (CDCl₃): δ-0.08-0.00 (m, 18H), 0.85 (t, J=8.1 Hz, 4H), 1.17 (t,J=7.2 Hz, 6H), 3.41 (t, J=8.1 Hz, 4H), 3.65 (s, 4H), 4.21 (q, J=7.2 Hz,4H), 5.12 (s, 4H), 6.86 (d, J=1.5 Hz, 2H), 6.93 (d, J=1.5 Hz, 2H).

EXAMPLE 53-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl)-2-[(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl)methyl]propanoicAcid

To an ethanol (7 mL) solution of the compound (1.60 g) produced inExample 4, an aqueous 5N sodium hydroxide solution (7 mL) was added. Thereaction solution was heated at reflux for 3 hours. The reactionsolution was concentrated under reduced pressure. 5N hydrochloric acidwas added to the residue so as to adjust the pH to 5. The aqueous layerwas saturated by adding sodium chloride and the solution was extractedthree times with dichloromethane (50 mL). The combined organic layer wasdried over anhydrous magnesium sulfate. After removing the anhydrousmagnesium sulfate by filtration, the filtrate was concentrated. Theresidue was purified by silica gel chromatography (ethylacetate→dichloromethane:methanol: 28% aqueous ammonia=80:20:3) to obtainthe title compound (828 mg) having the following physical properties.

TLC: Rf 0.36(dichloromethane:methanol:28% aqueous ammonia=80:20:3);

NMR (CDCl₃): δ-0.05-1.12 (m, 18H), 0.93 (t, J=8.4 Hz, 4H), 3.22-3.65 (m,9H), 5.48 (s, 4H), 6.98-7.08 (m, 4H).

EXAMPLE 6N-methoxy-N-methyl-3-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl)-2-[(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl)methyl]propanamide

To a dichloromethane (5 mL) solution of the compound (488 mg) producedin Example 5, methoxymethylamine hydrochloride (156 mg),N-methylmorpholine (0.34 mL),1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide (376 mg) and1-hydroxybenzimidazole (216 mg) were added in this order. The reactionsolution was stirred at room temperature for 15 hours. To the reactionsolution, water (10 mL) was added. The aqueous layer was extracted twicewith dichloromethane (50 mL). The combined organic layer was dried overanhydrous magnesium sulfate. After removing the anhydrous magnesiumsulfate by filtration, the filtrate was concentrated. The residue waspurified by silica gel chromatography (ethyl acetate:methanol: 28%aqueous ammonia=1:0:0→100:10:1) to obtain the title compound (510 mg)having the following physical properties.

TLC: Rf 0.60 (ethyl acetate:methanol:28% aqueous ammonia=90:5:1);

NMR (CDCl₃): δ-0.05-0.20 (m, 18H), 0.89 (m, 4H), 2.95 (dd, J=15.0, 7.2Hz, 2H), 3.13 (s, 3H), 3.15 (dd, J=15.0, 7.8 Hz, 2H), 3.46 (t, J=8.1 Hz,4H), 3.67 (s, 3H), 4.00 (m, 1H), 5.18 (m, 2H), 5.33 (m, 2H), 6.88 (d,J=1.5 Hz, 2H), 6.90 (d, J=1.5 Hz, 2H).

EXAMPLE 7 [(4-bromobenzyl)oxy](tert-butyl)dimethylsilane

To a dimethylformamide (30 mL) solution of (4-bromophenyl)methanol (3.00g), imidazole (2.18 g) and tert-butyldimethylsilyl chloride (2.89 g)were added in this order. The reaction solution was stirred at roomtemperature for one hour. To the reaction solution, water (10 mL) wasadded and the aqueous layer was extracted twice with ethyl acetate (50mL). The combined organic layer was washed in turn with 1N hydrochloricacid (10 mL) and saturated sodium chloride solution (10 mL) and thendried over anhydrous magnesium sulfate. After removing the anhydrousmagnesium sulfate by filtration, the filtrate was concentrated. Theresidue was purified by silica gel chromatography (n-hexane:ethylacetate=1:0→9:1) to obtain the title compound (3.77 g) having thefollowing physical properties.

TLC: Rf 0.90 (ethyl acetate:methanol=4:1);

NMR (CDCl₃): δ 0.09 (s, 6H), 0.93 (s, 9H), 4.68 (s, 2H), 7.19 (d, J=8.1Hz, 2H), 7.45 (d, J=8.1 Hz, 2H).

EXAMPLE 81-[4-({[tert-butyl(dimethyl)silyl]oxy}methyl)phenyl]-3-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl)-2-[(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl)methyl]propan-1-one

To an anhydrous tetrahydrofuran (20 mL) solution of the compound (3.01g) produced in Example 7, n-butyl lithium (1.6N n-hexanesolution, 8.1mL) was added at −78° C. The reaction solution was stirred at −78° C.for 30 minutes.

To an anhydrous tetrahydrofuran (5 mL) solution of the compound (255 mg)produced in Example 6, a preliminarily prepared lithium reagent (4 mL)was slowly added at −78° C. The reaction solution was stirred at roomtemperature for one hour. To the reaction solution, an aqueous ammoniumchloride solution (10 mL) and 1N hydrochloric acid (10 mL) were added.The aqueous layer was extracted twice with ethyl acetate (50 mL). Thecombined organic layer was washed with saturated sodium chloridesolution and then dried over anhydrous magnesium sulfate. After removingthe anhydrous magnesium sulfate by filtration, the filtrate wasconcentrated. The residue was purified by silica gel chromatography(ethyl acetate:methanol: 28% aqueous ammonia=1:0:0→100:5:1) to obtainthe title compound (275 mg) having the following physical properties.

TLC: Rf 0.67 (ethyl acetate:methanol:28% aqueous ammonia=19:1:0.05);

NMR (CDCl₃): δ-0.05-0.00 (m, 18H), 0.09 (s, 6H), 0.86 (m, 4H), 0.96 (s,9H), 3.03 (dd, J=15.3, 6.9 Hz, 2H), 3.19 (dd, J=15.3, 7.2 Hz, 2H), 3.42(m, 4H), 4.75 (s, 2H), 4.78 (m, 1H), 5.13 (d, J=11.1 Hz, 2H), 5.23 (d,J=11.1 Hz, 2H), 6.80 (d, J=1.2 Hz, 2H), 6.86 (d, J=1.2 Hz, 2H), 7.35 (d,J=8.4 Hz, 2H), 7.96 (d, J=8.4 Hz, 2H).

EXAMPLE 91-[4-(hydroxymethyl)phenyl]-3-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl)-2-[(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl)methyl]propan-1-one

To a tetrahydrofuran (2 mL) solution of the compound (56 mg) produced inExample 8, tetrahydroammonium fluoride (1N tetrahydrofuran solution, 1.5mL) was added. The reaction solution was stirred at room temperature for30 minutes. To the reaction solution, water (5 mL) was added. Theaqueous layer was washed twice with dichloromethane (20 mL). Thecombined organic layer was washed with saturated sodium chloridesolution and the dried over anhydrous magnesium sulfate. After removingthe anhydrous magnesium sulfate by filtration, the filtrate wasconcentrated. The residue was purified by silica gel chromatography(ethyl acetate:methanol: 28% aqueous ammonia=1:0:0→100:10:1) to obtainthe title compound (48 mg) having the following physical properties.

TLC: Rf 0.30 (ethyl acetate:methanol:28% aqueous ammonia=19:1:0.05);

NMR (CDCl₃): δ-0.05-0.00 (m, 18H), 0.87 (m, 4H), 3.03 (dd, J=15.6, 6.9Hz, 2H), 3.20 (dd, J=15.6, 7.2 Hz, 2H), 3.46 (m, 4H), 4.73 (s, 2H), 4.78(m, 1H), 5.13 (d, J=11.1 Hz, 2H), 5.23 (d, J=11.1 Hz, 2H), 6.79 (m, 2H),6.83 (m, 2H), 7.37 (d, J=8.1 Hz, 2H), 7.93 (d, J=8.1 Hz, 2H).

EXAMPLE 104-{3-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl)-2-[(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl)methyl]propanoyl}benzaldehyde

To a solution (ethyl acetate:dimethyl sulfoxide=3:2 (1.25 mL)) of thecompound (48 mg) produced in Example 9, triethylamine (0.12 mL) and asulfur trioxide-pyridine complex (39 mg) were added. The reactionsolution was stirred at room temperature for one hour. To the reactionsolution, water (5 mL) was added. The aqueous layer was extracted twicewith ethyl acetate (20 mL). The combined organic layer was washed withsaturated sodium chloride solution and then dried over anhydrousmagnesium sulfate. After removing the anhydrous magnesium sulfate byfiltration, the filtrate was concentrated. The residue was purified bysilica gel chromatography (ethyl acetate:methanol: 28% aqueousammonia=1:0:0→100:10:1) to obtain the title compound (30 mg) having thefollowing physical properties.

TLC: Rf 0.59 (ethyl acetate:methanol:28% aqueous ammonia=19:1:0.05);

NMR (CDCl₃): δ-0.05-0.00 (m, 18H), 0.87 (m, 4H), 3.06 (dd, J=15.6, 6.6Hz, 2H), 3.22 (dd, J=15.2, 7.8 Hz, 2H), 3.44 (m, 4H), 4.85 (m, 1H), 5.14(d, J=10.8 Hz, 2H), 5.23 (d, J=10.8 Hz, 2H), 6.81 (d, J=1.5 Hz, 1H),6.83 (d, J=1.5 Hz, 2H), 7.90 (d, J=8.4 Hz, 2H), 8.13 (d, J=8.4 Hz, 2H),10.1 (s, 1H).

EXAMPLE 114-[3-(1H-imidazol-2-yl)-2-(1H-imidazol-2-ylmethyl)propanoyl]benzaldehyde

To an aqueous 95% trifluoroacetic acid solution (1 mL) solution of thecompound (100 mg) produced in Example 10 was stirred at 50° C. for onehour. The reaction solution was concentrated under reduced pressure. Tothe residue, methanol (20 mL) was added and then MP-carbonate (tradename, manufactured by Argonaut Technologies Inc., product number:800267,100 mg) was added to the solution, followed by shaking for 30minutes. The resin was removed by filtration and the filtrate wasconcentrated under reduced pressure. Without purifying the residue, thetitle compound having the following physical properties was obtained.

TLC: Rf 0.63 (ethyl acetate:methanol:28% aqueous ammonia=80:20:2);

NMR (CDCl₃): δ 2.82 (d, J=14.4, 7.2 Hz, 2H), 3.15 (dd, J=14.4, 4.5 Hz,2H), 4.03 (m, 1H), 7.05 (m, 4H), 8.01 (d, J=8.4 Hz, 2H), 8.20 (d, J=8.4Hz, 2H), 10.1 (s, 1H).

EXAMPLE 12 Tert-butyl8-[(3-methyl-2-thienyl)methyl]-2,8-diazaspiro[4.5]decane-2-carboxylate

To a 1% acetic acid-dimethylformamide (10 mL) solution of tert-butyl2,8-diazaspiro[4.5]decane-2-carboxylate (1.28 g) and3-methylthiophene-2-carboaldehyde (700 mg), sodium triacetoxyborohydride(1.96 g) was added. The reaction solution was stirred at roomtemperature for 15 hours. To the reaction solution, an aqueous 5N sodiumhydroxide solution (10 mL) was added. The aqueous layer was washed twicewith dichloromethane (100 mL) The combined organic layer was washed withsaturated sodium chloride solution (50 mL) and then dried over anhydrousmagnesium sulfate. After removing the anhydrous magnesium sulfate byfiltration, the filtrate was concentrated. The residue was purified bysilica gel chromatography (n-hexane:ethyl acetate=1:1→1:3) to obtain thetitle compound (1.14 g) having the following physical properties.

TLC: Rf 0.23 (ethyl acetate:methanol=1:2);

NMR (CDCl₃): δ 1.45 (s, 9H), 1.50-1.75 (m, 6H), 2.18 (s, 3H), 2.25-2.45(m, 2H), 2.45-2.63 (m, 2H), 3.06-3.22 (m, 2H), 3.28-3.42 (m, 2H), 3.60(s, 2H), 6.76 (d, J=5.1 Hz, 1H) 7.10 (d, J=5.1 Hz, 1H).

EXAMPLE 13 8-[(3-methyl-2-thienyl)methyl]-2,8-diazaspiro[4.5]decane

To a methanol (5 mL) solution of the compound (1.14 g) produced inExample 12, a 1,4-dioxane solution (3 mL) of 4N hydrogen chloride wasadded. The reaction solution was stirred at room temperature for 3hours. The reaction solution was concentrated under reduced pressure. Tothe residue, methanol (30 mL) was added and then MP-carbonate (tradename, manufactured by Argonaut Technologies Inc., product number:800267, 100 mg) was added, followed by stirring for 30 minutes. Afterremoving the resin by filtration, the filtrate was concentrated underreduced pressure. Without purifying the residue, the title compound (768mg) having the following physical properties was obtained.

TLC: Rf 0.06 (dichloromethane:methanol:28% aqueous ammonia=80:20:2);

NMR (CDCl₃): δ 1.50-1.72 (m, 6H), 2.18 (s, 3H), 2.38-2.58 (m, 4H), 2.83(s, 2H), 3.09 (t, J=7.5 Hz, 2H), 3.60 (s, 2H), 6.78 (d, J=5.1 Hz, 1H),7.12 (d, J=5.1 Hz, 1H).

EXAMPLE 143-(1H-imidazol-2-yl)-2-(1H-imidazol-2-ylmethyl)-1-[4-({8-[(3-methyl-2-thienyl)methyl]-2,8-diazaspiro[4.5]dec-2-yl}methyl)phenyl]propan-1-one

Using the compound (64 mg) produced in Example 13 and the compound (54mg) produced in Example 11, the same operation as in Example 12 wasperformed. The resulting residue was purified by silica gelchromatography (ethyl acetate:methanol:28% aqueous ammonia=100:10:2) toobtain the title compound (14 mg) having the following physicalproperties.

TLC: Rf 0.48 (ethyl acetate:methanol:28% aqueous ammonia=90:10:1);

NMR (CDCl₃): δ 1.55-1.72 (m, 6H), 2.17 (s, 3H), 2.30-2.55 (m, 6H), 2.60(t, J=7.5 Hz, 2H), 2.79 (dd, J=14.7, 5.7 Hz, 2H), 3.16 (dd, J=14.7, 4.2Hz, 2H), 3.57 (s, 2H), 3.64 (s, 2H), 4.04 (m, 1H), 6.77 (d, J=5.1 Hz,1H), 7.05 (s, 4H), 7.11 (d, J=5.1 Hz, 1H), 7.48 (d, J=8.1 Hz, 2H), 8.03(d, J=8.1 Hz, 2H).

EXAMPLE 14(1)-Example 14(2)

Except for using the corresponding amine in place of the compoundproduced in Example 13, the same operation as in Example 14 wasperformed to obtain the following compounds.

EXAMPLE 14(1)1-[4-({[4-(dipropylamino)butyl]amino}methyl)phenyl]-3-(1H-imidazol-2-yl)-2-(1H-imidazol-2-ylmethyl)-1-propanone

TLC: Rf 0.35 (dichloromethane:methanol:28% aqueous ammonia=8:2:0.4);

NMR (CDCl₃): δ 0.86 (t, J=7.2 Hz, 6H), 1.38-1.60 (m, 8H), 2.30-2.48 (m,6H), 2.60-2.68 (m, 2H), 2.77 (dd, J=14.4, 7.2 Hz, 2H), 3.16 (dd, J=14.4,4.5 Hz, 2H), 3.87 (s, 2H), 4.00 (m, 1H), 7.06 (s, 4H), 7.48 (d, J=8.1Hz, 2H), 8.04 (d, J=8.1 Hz, 2H).

EXAMPLE 14(2)1-{4-[({trans-4-[cyclohexyl(propyl)amino]cyclohexyl}amino)methyl]phenyl}-3-(1H-imidazol-2-yl)-2-(1H-imidazol-2-ylmethyl)-1-propanone

TLC: Rf 0.45 (dichloromethane:methanol:28% aqueous ammonia=8:2:0.2);

NMR (CDCl₃): δ 0.84 (t, J=7.2 Hz, 3H), 1.00-2.10 (m, 20H), 2.30-2.82 (m,5H), 2.77 (dd, J=14.1, 7.2 Hz, 2H), 3.15 (dd, J=14.1 Hz, 4.5 Hz, 2H),3.88 (s, 2H), 4.01 (m, 1H), 7.06 (s, 4H), 7.47 (d, J=8.1 Hz, 2H), 8.03(d, J=8.1 Hz, 2H).

EXAMPLE 153-(1H-imidazol-2-yl)-2-(1H-imidazol-2-ylmethyl)-1-[4-({8-[(3-methyl-2-thienyl)methyl]-2,8-diazaspiro[4.5]dec-2-yl}methyl)phenyl]-1-propanol

To a methanol (2 mL) solution of the compound (26 mg) produced inExample 14, sodium borohydride (26 mg) was added. The reaction solutionwas stirred at room temperature for 30 minutes. To the reactionsolution, water (10 mL) was added. The aqueous layer was extracted twicewith dichloromethane (20 mL). The combined organic layer was washed withsaturated sodium chloride solution (20 mL) and then dried over anhydrousmagnesium sulfate. After removing the anhydrous magnesium sulfate byfiltration, the filtrate was concentrated. The residue was purified bysilica gel chromatography (ethyl acetate:methanol: 28% aqueousammonia=8:2:0.4) to obtain the title compound (25 mg) having thefollowing physical properties.

TLC: Rf 0.22 (ethyl acetate:methanol:28% aqueous ammonia=9:1:0.2);

NMR (CDCl₃): δ 1.50-1.70 (m, 6H), 2.17 (s, 3H), 2.25-2.90 (m, 11H), 3.05(dd, J=14.7, 5.7 Hz, 2H), 3.57 (s, 2H), 3.59 (s, 2H), 4.46 (d, J=6.6 Hz,1H), 6.77 (d, J=5.1 Hz, 1H), 6.97 (d, J=2.7 Hz, 4H), 7.10 (d, J=5.1 Hz,1H), 7.20-7.32 (m, 4H).

EXAMPLE 15(1)-EXAMPLE 15(2)

Except for using the corresponding carbonyl compound in place of thecompound produced in Example 14, the same operation as in Example 15 wasperformed to obtain the following compounds.

EXAMPLE 15(1)1-[4-({[4-(dipropylamino)butyl]amino}methyl)phenyl]-3-(1H-imidazol-2-yl)-2-(1H-imidazol-2-ylmethyl)-1-propanol

TLC: Rf 0.24 (dichloromethane:methanol:28% aqueous ammonia=8:2:0.4);

NMR (CDCl₃): δ 0.87 (t, J=7.2 Hz, 6H), 1.38-1.80 (m, 8H), 2.20-2.88 (m,12H), 2.98 (m, 1H), 3.83 (s, 2H), 4.50 (m, 1H), 6.85-7.00 (m, 4H),7.10-7.35 (m, 4H).

EXAMPLE 15(2)1-{4-[({trans-4-[cyclohexyl(propyl)amino]cyclohexyl}amino)methyl]phenyl}-3-(1H-imidazol-2-yl)-2-(1H-imidazol-2-ylmethyl)-1-propanol

TLC: Rf 0.44 (dichloromethane:methanol:28% aqueous ammonia=8:2:0.2);

NMR (CDCl₃): δ 0.83 (t, J=7.5 Hz, 3H), 1.00-2.72 (m, 28H), 2.92 (m, 2H),3.77 (s, 2H), 4.38 (d, J=5.7 Hz, 1H), 6.82-6.98 (m, 4H), 7.10-7.28 (m,4H).

EXAMPLE 16Tert-butyl[4-({8-[(3-methyl-2-thienyl)methyl]-2,8-diazaspiro[4.5]dec-2-yl}methyl)benzyl]carbamate

Except for using the compound (150 mg) produced in Example 13 in placeof tert-butyl 2,8-diazaspiro[4.5]decane-2-carboxylate and using4-(N-tert-butoxyaminomethyl)benzaldehyde (169 mg) in place of3-methylthiophene-2-carboaldehyde, the same operation as in Example 12was performed to obtain the title compound (211 mg) having the followingphysical properties.

TLC: Rf 0.76 (ethyl acetate:methanol:28% aqueous ammonia=9:1:0.2);

NMR (CDCl₃): δ 1.46 (s, 9H), 1.50-1.75 (m, 6H), 2.17 (s, 3H), 2.28-2.50(m, 6H), 2.55 (t, J=6.9 Hz, 2H), 3.55 (s, 2H), 3.56 (s, 2H), 4.20-4.40(m, 2H), 4.81 (m, 1H), 6.77 (d, J=5.1 Hz, 1H), 7.11 (d, J=5.1 Hz, 1H),7.22 (d, J=7.8 Hz, 2H), 7.31 (d, J=7.8 Hz, 2H).

EXAMPLE 171-[4-({8-[(3-methyl-2-thienyl)methyl]-2,8-diazaspiro[4.5]dec-2-yl}methyl)phenyl]methanamine

To a methanol (5 mL) solution of the compound (211 mg) produced inExample 16, 4N hydrogen chloride-1,4-dioxane (5 mL) was added. Thereaction solution was stirred at room temperature for one hour. Thereaction solution was concentrated under reduced pressure. To theresidue, an aqueous 5N sodium hydroxide solution (10 mL) was added. Theaqueous layer was extracted twice with dichloromethane (20 mL). Thecombined organic layer was washed with saturated sodium chloridesolution (20 mL) and then dried over anhydrous magnesium sulfate. Afterremoving the anhydrous magnesium sulfate by filtration, the filtrate wasconcentrated. Without purifying the residue, the title compound (140 mg)having the following physical properties was obtained.

TLC: Rf 0.13 (ethyl acetate:methanol:28% aqueous ammonia=9:1:0.2);

NMR (CDCl₃): δ 1.40-1.75 (m, 6H), 2.17 (s, 3H), 2.28-2.52 (m, 6H), 2.56(t, J=6.9 Hz, 2H), 3.56 (s, 4H), 3.86 (s, 2H), 6.77 (d, J=5.4 Hz, 1H),7.11 (d, J=5.4 Hz, 1H), 7.22-7.38 (m, 4H).

EXAMPLE 183-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl)-2-[(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl)methyl]-1-propanol

To a tetrahydrofuran (2 mL) suspension of lithium aluminum hydride (16mg), a tetrahydrofuran (1 mL) solution of the compound (100 mg) producedin Example 5 was added. The reaction solution was stirred at roomtemperature for 15 minutes. To the reaction solution, an aqueoussaturated sodium sulfate solution (1 mL) was added. The reactionsolution was diluted with ethyl acetate (5 mL) and then dried overanhydrous magnesium sulfate. After removing the anhydrous magnesiumsulfate by filtration through Celite (trade name), the filtrate wasconcentrated. Without purifying the residue, the title compound (80 mg)having the following physical properties was obtained.

TLC: Rf 0.36 (ethyl acetate:methanol:28% aqueous ammonia=9:1:0.1);

NMR (CDCl₃): δ-0.03 (s, 18H), 0.87 (t, J=8.1 Hz, 4H), 2.58 (m, 1H),2.82-2.98 (m, 4H), 3.45 (t, J=8.1 Hz, 4H), 3.63 (d, J=3.9 Hz, 2H), 5.16(d, J=11.1 Hz, 2H), 5.21 (d, J=11.1 Hz, 2H), 6.89 (d, J=1.2 Hz, 2H),6.93 (d, J=1.2 Hz, 2H).

EXAMPLE 193-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl)-2-[(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl)methyl]propanal

Except for using the compound (350 mg) produced in Example 18 in placeof the compound produced in Example 9, the same operation as in Example10 was performed to obtain the title compound (370 mg) having thefollowing physical properties.

TLC: Rf 0.63 (ethyl acetate:methanol:28% aqueous ammonia=9:1:0.1);

NMR (CDCl₃): δ-0.03 (s, 18H), 0.87 (t, J=8.4 Hz, 4H), 3.07 (dd, J=15.9,6.9 Hz, 2H), 3.25 (dd, J=15.9, 6.6 Hz, 2H), 3.45 (t, J=8.4 Hz, 4H), 3.58(m, 1H), 5.19 (s, 4H), 6.89 (d, J=1.5 Hz, 2H), 6.92 (d, J=1.5 Hz, 2H),9.96 (s, 1H).

EXAMPLE 20N-[4-({8-[(3-methyl-2-thienyl)methyl]-2,8-diazaspiro[4.5]dec-2-yl}methyl)benzyl]-3-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl)-2-[(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl)methyl]-1-propanamine

Except for using the compound (140 mg) produced in Example 17 in placeof tert-butyl 2,8-diazaspiro[4.5]decane-2-carboxylate and using thecompound (211 mg) produced in Example 19 in place of3-methylthiophene-2-carboaldehyde, the same operation as in Example 12was performed to obtain the title compound (300 mg) having the followingphysical properties.

TLC: Rf 0.51 (ethyl acetate:methanol:28% aqueous ammonia=8:2:0.2);

NMR (CDCl₃): δ-0.03 (s, 18H), 0.87 (t, J=8.4 Hz, 4H), 1.50-1.70 (m, 6H),2.17 (s, 3H), 2.30-2.45 (m, 6H), 2.54 (t, J=6.9 Hz, 2H), 2.58-2.68 (m,3H), 2.80-2.98 (m, 4H), 3.45 (t, J=8.4 Hz, 4H), 3.54 (s, 2H), 3.58 (s,2H), 3.71 (s, 2H), 5.18 (d, J=10.8 Hz, 2H), 5.26 (d, J=10.8 Hz, 2H),6.76 (d, J=5.1 Hz, 1H), 6.88 (d, J=1.5 Hz, 2H), 6.91 (d, J=1.5 Hz, 2H),7.10 (d, J=5.1 Hz, 1H), 7.22 (s, 4H).

EXAMPLE 213-(1H-imidazol-2-yl)-2-(1H-imidazol-2-ylmethyl)-N-[4-({8-[(3-methyl-2-thienyl)methyl]-2,8-diazaspiro[4.5]dec-2-yl}methyl)benzyl]-1-propanamine

An aqueous 95% trifluoroacetic acid solution (4.2 mL) of the compound(38 mg) produced in Example 20 was stirred at 60° C. for 4 hours. Thereaction solution was concentrated under reduced pressure. To theresidue, an aqueous 5N sodium hydroxide solution (10 mL) was added. Theaqueous layer was extracted twice with dichloromethane (20 mL). Thecombined organic layer was washed with saturated sodium chloridesolution (20 mL) and then dried over anhydrous magnesium sulfate. Afterremoving the anhydrous magnesium sulfate by filtration, the filtrate wasconcentrated. The residue was purified by silica gel chromatography(ethyl acetate:methanol:28% aqueous ammonia=8:2:0.4) to obtain the titlecompound (13 mg) having the following physical properties.

TLC: Rf 0.35 (ethyl acetate:methanol:28% aqueous ammonia=8:2:0.2);

NMR (CDCl₃): δ 1.52-1.70 (m, 6H), 2.17 (s, 3H), 2.32-2.50 (m, 6H), 2.50(m, 1H), 2.61 (t, J=6.9 Hz, 2H), 2.71-2.95 (m, 6H), 3.58 (s, 2H), 3.62(s, 2H), 3.92 (s, 2H), 6.77 (d, J=5.1 Hz, 1H), 6.87 (s, 4H), 7.12 (d,J=5.1 Hz, 1H), 7.28-7.40 (m, 4H).

EXAMPLE 21 (1)N-[3-(1H-imidazol-2-yl)-2-(1H-imidazol-2-ylmethyl)propyl]-4-({8-[(3-methyl-2-thienyl)methyl]-2,8-diazaspiro[4.5]dec-2-yl}methyl)aniline

Except for using the corresponding amine in place of the compoundproduced in Example 17 in Example 20, the same operation as in Example20→Example 21 was performed to obtain the title compound having thefollowing physical properties.

TLC: Rf 0.39 (ethyl acetate:methanol:28% aqueous ammonia=8:2:0.2);

NMR (CDCl₃): δ 1.50-1.70 (m, 6H), 2.17 (s, 3H), 2.28-2.78 (m, 13H), 3.00(d, J=6.6 Hz, 2H), 3.54 (s, 2H), 3.56 (s, 2H), 6.53 (d, J=8.4 Hz, 2H),6.77 (d, J=5.1 Hz, 1H), 7.02 (s, 4H), 7.06-7.15 (m, 3H).

EXAMPLE 22N-methyl-N-[4-({8-[(3-methyl-2-thienyl)methyl]-2,8-diazaspiro[4.5]dec-2-yl}methyl)benzyl]-3-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl)-2-[(1-{[(trimethylsilyl)methoxy]methyl}-1H-imidazol-2-yl)methyl]-1-propanamine

To a 10% acetic acid-dimethylformamide (2 mL) solution of the compound(100 mg) produced in Example 20, an aqueous 37% formaldehyde solution(28 μL) and sodium triacetoxyborohydride (80 mg) were added. Thereaction solution was stirred at room temperature for 30 minutes. To thereaction solution, an aqueous 5N sodium hydroxide solution (10 mL) wasadded. The aqueous layer was extracted twice with dichloromethane (20mL). The combined organic layer was washed with saturated sodiumchloride solution (20 mL) and then dried over anhydrous magnesiumsulfate. After removing the anhydrous magnesium sulfate by filtration,the filtrate was concentrated. Without purifying the residue, the titlecompound (100 mg) having the following physical properties was obtained.

TLC: Rf 0.68 (ethyl acetate:methanol:28% aqueous ammonia=8:2:0.2);

EXAMPLE 233-(1H-imidazol-2-yl)-2-(1H-imidazol-2-ylmethyl)-N-methyl-N-[4-({8-[(3-methyl-2-thienyl)methyl]-2,8-diazaspiro[4.5]dec-2-yl}methyl)benzyl]-1-propanamine

Except for using the compound (100 mg) produced in Example 22 in placeofN-[4-({8-[(3-methyl-2-thienyl)methyl]-2,8-diazaspiro[4.5]dec-2-yl}methyl)benzyl]-3-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl)-2-[(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl)methyl]-1-propaneamine,the same operation as in Example 21 was performed to obtain the titlecompound (100 mg) having the following physical properties.

TLC: Rf 0.49 (ethyl acetate:methanol:28% aqueous ammonia=8:2:0.4);

NMR (CDCl₃): δ 1.50-1.72 (m, 6H), 2.00-2.75 (m, 21H), 3.48 (s, 2H), 3.57(s, 2H), 3.62 (s, 2H), 6.77 (d, J=5.1 Hz, 1H), 6.84 (s, 4H), 7.11 (d,J=5.1 Hz, 1H), 7.25-7.42 (m, 4H).

EXAMPLE 24N-[4-({8-[(3-methyl-2-thienyl)methyl]-2,8-diazaspiro[4.5]dec-2-yl}methyl)benzyl]-N-{3-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl)-2-[(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl)methyl]propyl}acetamide

To a dichloromethane (3 mL) solution of the compound (100 mg) producedin Example 23, pyridine (31 μL) and anhydrous acetic acid (24 μL) wereadded. The reaction solution was stirred at room temperature for 30minutes. To the reaction solution, water (10 mL) was added. The aqueouslayer was extracted twice with ethyl acetate (20 mL). The combinedorganic layer was washed with saturated sodium chloride solution (20 mL)and then dried over anhydrous magnesium sulfate. After removing theanhydrous magnesium sulfate by filtration, the filtrate wasconcentrated. Without purifying the residue, the title compound (100 mg)having the following physical properties was obtained.

TLC: Rf 0.61 (ethyl acetate:methanol:28% aqueous ammonia=8:2:0.2);

NMR (CDCl₃): δ-0.03 (s, 18H), 0.70-0.98 (m, 4H), 1.60-1.90 (m, 6H),1.90-2.30 (m, 6H), 2.35-3.10 (m, 9H), 3.25-3.98 (m, 14H), 4.42-4.65 (m,2H), 5.02-5.28 (m, 4H), 6.68-7.50 (m, 10H).

EXAMPLE 25N-[3-(1H-imidazol-2-yl)-2-(1H-imidazol-2-ylmethyl)propyl]-N-[4-({8-[(3-methyl-2-thienyl)methyl]-2,8-diazaspiro[4.5]dec-2-yl}methyl)benzyl]acetamide

Except for using the compound (100 mg) produced in Example 24 in placeof the compound produced in Example 20, the same operation as in Example21 was performed to obtain the title compound (17 mg) having thefollowing physical properties.

TLC: Rf 0.54 (ethyl acetate:methanol:28% aqueous ammonia=8:2:0.4);

NMR (CDCl₃): δ 1.50-1.70 (m, 6H), 2.17 (s, 3H), 2.26 (s, 3H), 2.28-2.84(m, 13H), 3.34 (m, 2H), 3.59 (s, 2H), 3.62 (s, 2H), 4.63 (s, 2H), 6.77(d, J=5.1 Hz, 1H), 7.06 (s, 4H), 7.08-7.18 (m, 3H), 7.34 (d, J=8.1 Hz,2H).

EXAMPLE 25(1)N-{4-[(8-cyclohexyl-2,8-diazaspiro[4.5]dec-2-yl)methyl]phenyl}-N-[3-(1H-imidazol-2-yl)-2-(1H-imidazol-2-ylmethyl)propyl]acetamide

Except for using the corresponding amine (66 mg) in place of thecompound produced in Example 17 in Example 20, the same operation as inExample 20→Example 24→Example 21 was performed to obtain the titlecompound (23 mg) having the following physical properties.

TLC: Rf 0.26 (ethyl acetate:methanol:28% aqueous ammonia=8:2:0.4);

NMR (CDCl₃): δ 1.00-1.98 (m, 16H), 1.92 (s, 3H), 2.06-2.65 (m, 12H),2.70 (dd, J=14.4, 4.2 Hz, 2H), 3.60 (s, 2H), 3.62-3.78 (m, 2H),6.92-7.14 (m, 4H), 7.06 (d, J=8.4 Hz, 2H), 7.38 (d, J=8.4 Hz, 2H), 12.61(brs, 2H).

EXAMPLE 262-[4-(diethoxymethyl)benzyl]-8-isobutyl-2,8-diazaspiro[4.5]decane

To a 10% acetic acid-dimethylformamide (10 mL) solution of8-isobutyl-2,8-diazaspiro[4.5]decane (600 mg) and4-(diethoxymethyl)benzaldehyde (661 mg), sodium triacetoxyborohydride(1.30 g) was added. The reaction solution was stirred at roomtemperature for 14 hours. To the reaction solution, an aqueous 5N sodiumhydroxide solution (10 mL) was added. The aqueous layer was extractedtwice with dichloromethane (20 mL). The combined organic layer waswashed with saturated sodium chloride solution (20 mL) and then driedover anhydrous magnesium sulfate. After removing the anhydrous magnesiumsulfate by filtration, the filtrate was concentrated. The residue waspurified by silica gel chromatography (ethyl acetate:methanol: 28%aqueous ammonia=1:0:0→100:5:1→100:10:2) to obtain the title compound(730 mg) having the following physical properties.

TLC: Rf 0.77 (ethyl acetate:methanol:28% aqueous ammonia=9:1:0.1);

NMR (CDCl₃): δ 0.87 (d, J=6.6 Hz, 6H), 1.24 (t, J=7.2 Hz, 6H), 1.50-1.64(m, 6H), 1.78 (m, 1H), 2.01 (d, J=7.2 Hz, 2H), 2.20-2.32 (m, 4H), 2.34(s, 2H), 2.56 (t, J=7.2 Hz, 2H), 3.45-3.68 (m, 6H), 5.49 (s, 1H),7.25-7.38 (m, 2H), 7.38-7.45 (m, 2H).

EXAMPLE 274-[(8-isobutyl-2,8-diazaspiro[4.5]dec-2-yl)methyl]benzaldehyde

To a dichloromethane (10 mL) solution of the compound (730 mg) producedin Example 26, trifluoroacetic acid (5 mL) was added, followed bystirring at room temperature for one hour. To the reaction solution, anaqueous 5N sodium hydroxide solution (10 mL) was added. The aqueouslayer was extracted twice with dichloromethane (20 mL). The combinedorganic layer was washed in turn with water (20 mL) and saturated sodiumchloride solution (20 mL), and then dried over anhydrous magnesiumsulfate. After removing the anhydrous magnesium sulfate by filtration,the filtrate was concentrated. Without purifying the residue, the titlecompound (611 mg) having the following physical properties was obtained.

TLC: Rf 0.80 (ethyl acetate:methanol:28% aqueous ammonia=8:2:0.4);

NMR (CDCl₃): δ 0.88 (d, J=6.3 Hz, 6H), 1.48-1.68 (m, 6H), 1.78 (m, 1H),2.00-2.14 (m, 2H), 2.20-2.40 (m, 4H), 2.37 (s, 2H), 2.58 (t, J=7.2 Hz,2H), 3.65 (s, 2H), 7.49 (d, J=8.4 Hz, 2H), 7.81 (d, J=8.4 Hz, 2H), 9.99(s, 1H).

EXAMPLE 28N-benzyl-3-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl)-2-[(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl)methyl]-1-propanamine

Except for using the compound (4.50 g) produced in Example 19 in placeof 4-(diethoxymethyl)benzaldehyde and using 1-phenylmethaneamine (3.40g) in place of 8-isobutyl-2,8-diazaspiro[4.5]decane, the same operationas in Example 26 was performed to obtain the title compound (3.41 g)having the following physical properties.

TLC: Rf 0.46 (ethyl acetate:methanol:28% aqueous ammonia=8:2:0.4);

NMR (CDCl₃): δ-0.03 (s, 18H), 0.87 (t, J=8.4 Hz, 4H), 2.50-2.65 (m, 3H),2.80-2.98 (m, 4H), 3.44 (t, J=8.4 Hz, 4H), 3.72 (s, 2H), 5.18 (d, J=10.8Hz, 2H), 5.26 (d, J=10.8 Hz, 2H), 6.88 (d, J=1.5 Hz, 2H), 6.91 (d, J=1.5Hz, 2H), 7.18-7.40 (m, 5H).

EXAMPLE 293-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl)-2-[(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl)methyl]-1-propanamine

To an ethanol (80 mL) suspension of palladium hydroxide 20% supported oncarbon (2.40 g), an ethanol (20 mL) solution of the compound (2.41 g)produced in Example 28 was added. The atmosphere in the reaction systemwas replaced by hydrogen, followed by stirring at 50° C. for 2 hours.After removing the palladium hydroxide by filtering the reactionsolution through Celite (trade name), the filtrate was concentrated.Without purifying the residue, the title compound (1.42 g) having thefollowing physical properties was obtained.

TLC: Rf 0.46 (ethyl acetate:methanol:28% aqueous ammonia=8:2:0.4);

NMR (CDCl₃): δ-0.03 (s, 18H), 0.87 (t, J=8.4 Hz, 4H), 2.48 (m, 1H), 2.75(d, J=5.4 Hz, 2H), 2.80-2.94 (m, 4H), 3.46 (t, J=8.4 Hz, 4H), 5.20 (d,J=10.8 Hz, 2H), 5.27 (d, J=10.8 Hz, 2H), 6.89 (d, J=1.5 Hz, 2H), 6.93(d, J=1.5 Hz, 2H).

EXAMPLE 30N-{4-[(8-isobutyl-2,8-diazaspiro[4.5]dec-2-yl)methyl]benzyl}-3-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl)-2-[(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl)methyl]-1-propanamine

Except for using the compound (200 mg) produced in Example 29 in placeof 8-isobutyl-2,8-diazaspiro[4.5]decane and using the compound (135 mg)produced in Example 27 in place of 4-(diethoxymethyl)benzaldehyde, thesame operation as in Example 26 was performed to obtain the titlecompound (142 mg) having the following physical properties.

TLC: Rf 0.55 (ethyl acetate:methanol:28% aqueous ammonia=9:1:0.2);

NMR (CD₃OD): δ-0.03 (s, 18H), 0.86 (t, J=8.4 Hz, 4H), 0.90 (d, J=6.6 Hz,6H), 1.55-1.70 (m, 6H), 1.80 (m, 1H), 2.09 (d, J=6.9 Hz, 2H), 2.25-2.98(m, 15H), 3.40-3.60 (m, 6H), 3.67 (s, 2H), 5.20-5.32 (m, 4H), 6.85 (m,2H), 7.10 (m, 2H), 7.20-7.30 (m, 4H).

EXAMPLE 312-({4-[(8-isobutyl-2,8-diazaspiro[4.5]dec-2-yl)methyl]benzyl}{3-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl)-2-[(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl)methyl]propyl}amino)-2-oxoethylAcetate

To a dichloromethane (2 mL) solution of the compound (77 mg) produced inExample 30, triethylamine (140 μL) and acetoxyacetyl chloride (65 μL)were added. The reaction solution was stirred at room temperature for 3hours. To the reaction solution, water (10 mL) was added. The aqueouslayer was extracted twice with ethyl acetate (20 mL). The combinedorganic layer was washed with saturated sodium chloride solution (20 mL)and then dried over anhydrous magnesium sulfate. After removing theanhydrous magnesium sulfate by filtration, the filtrate wasconcentrated. The residue was purified by silica gel chromatography(n-hexane:ethyl acetate=1:1→ethyl acetate:methanol: 28% aqueousammonia=100:10:0→100:10:1) to obtain the title compound (50 mg) havingthe following physical properties.

TLC: Rf 0.73 (ethyl acetate:methanol:28% aqueous ammonia=9:1:0.2);

NMR (CDCl₃): δ-0.03 (s, 18H), 0.80-0.95 (m, 10H), 1.50-1.63 (m, 6H),1.78 (m, 1H), 1.78-2.20 (m, 11H), 2.57 (t, J=6.9 Hz, 2H), 2.60-3.62 (m,11H), 4.38-4.72 (m, 4H), 5.05-5.28 (m, 6H), 6.85-6.95 (m, 4H), 7.02-7.30(m, 4H).

EXAMPLE 322-hydroxy-N-[3-(1H-imidazol-2-yl)-2-(1H-imidazol-2-ylmethyl)propyl]-N-{4-[(8-isobutyl-2,8-diazaspiro[4.5]dec-2-yl)methyl]benzyl}acetamide

An aqueous 95% trifluoroacetic acid solution (2.2 mL) solution of thecompound (94 mg) produced in Example 31 was stirred at 50° C. for 3hours. The reaction solution was concentrated under reduced pressure. Tothe residue, a 2N potassium carbonate/methanol solution (2 mL) wasadded, followed by stirring at room temperature for 30 minutes. To thereaction solution, water (10 mL) was added. The aqueous layer wasextracted twice with dichloromethane (20 mL). The combined organic layerwas washed with saturated sodium chloride solution (20 mL) and thendried over anhydrous magnesium sulfate. After removing the anhydrousmagnesium sulfate by filtration, the filtrate was concentrated. Theresidue was purified by silica gel chromatography(dichloromethane:methanol: 28% aqueous ammonia=9:1:0.2) to obtain thetitle compound (22 mg) having the following physical properties.

TLC: Rf 0.28 (ethyl acetate:methanol:28% aqueous ammonia=8:2:0.4);

NMR (CDCl₃): δ 0.87 (d, J=6.6 Hz, 6H), 1.50-2.46 (m, 18H), 2.55 (t,J=6.9 Hz, 2H), 2.65-2.80 (m, 2H), 3.35-3.46 (m, 2H), 3.57 (s, 2H), 4.34(s, 2H), 4.44 (s, 2H), 7.04 (s, 4H), 7.06 (d, J=8.1 Hz, 2H), 7.34 (d,J=8.1 Hz, 2H).

EXAMPLE 33 Ethyl2-cyano-3-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl)-2-[(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl)methyl]propanoate

Except for using cyanoethyl acetate (1.00 g) in place of diethylmalonate, the same operation as in Example 4 was performed to obtain thetitle compound (2.50 g) having the following physical properties.

TLC: Rf 0.36 (ethyl acetate:methanol:28% aqueous ammonia=9:1:0.1);

NMR (CDCl₃): δ-0.03 (s, 18H), 0.89 (t, J=8.4 Hz, 4H), 1.29 (t, J=7.2 Hz,3H), 3.46 (t, J=8.4 Hz, 4H), 3.61 (s, 4H), 4.22-4.38 (m, 2H), 5.26 (d,J=10.8 Hz, 2H), 5.36 (d, J=10.8 Hz, 2H), 6.95 (d, J=1.5 Hz, 2H), 6.99(J=1.5 Hz, 2H).

EXAMPLE 343-amino-2,2-bis[(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl)methyl]-1-propanol

Except for using the compound (800 mg) produced in Example 33 in placeof the compound produced in Example 5, the same operation as in Example18 was performed to obtain the title compound (620 mg) having thefollowing physical properties.

TLC: Rf 0.29 (ethyl acetate:methanol:28% aqueous ammonia=8:2:0.2);

NMR (CDCl₃): δ-0.03 (s, 18H), 0.89 (d, J=8.4 Hz, 4H), 2.46 (s, 2H), 2.86(d, J=15.0 Hz, 2H), 2.98 (d, J=15.0 Hz, 2H), 3.25 (s, 2H), 3.48 (d,J=8.4 Hz, 4H), 5.26 (d, J=10.8 Hz, 2H), 5.42 (d, J=10.8 Hz, 2H),6.89-7.00 (m, 4H).

EXAMPLE 353-({4-[(8-cyclohexyl-2,8-diazaspiro[4.5]dec-2-yl)methyl]benzyl}amino)-2,2-bis[(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl)methyl]-1-propanol

Except for using the compound (111 mg) produced in Example 34 in placeof 8-isobutyl-2,8-diazaspiro[4.5]decane and using the correspondingaldehyde (92 mg) in place of 4-(diethoxymethyl)benzaldehyde, the sameoperation as in Example 26 was performed to obtain the title compound(100 mg) having the following physical properties.

TLC: Rf 0.39 (ethyl acetate:methanol:28% aqueous ammonia=8:2:0.4);

NMR (CDCl₃): δ-0.03 (s, 18H), 0.87 (t, J=8.4 Hz, 4H), 1.00-1.95 (m,16H), 2.15-2.60 (m, 11H), 2.88 (d, J=15.0 Hz, 2H), 3.01 (d, J=15.0 Hz,2H), 3.29 (s, 2H), 3.45 (t, J=8.4 Hz, 4H), 3.55 (s, 2H), 3.68 (s, 2H),5.25 (d, J=10.8 Hz, 2H), 5.38 (d, J=10.8 Hz, 2H), 6.90 (d, J=1.2 Hz,2H), 6.94 (d, J=1.2 Hz, 2H), 7.20-7.35 (m, 4H).

EXAMPLE 363-(acetyl{4-[(8-cyclohexyl-2,8-diazaspiro[4.5]dec-2-yl)methyl]benzyl}amino)-2,2-bis[(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl)methyl]propylAcetate

To a dichloromethane (2 mL) solution of the compound (33 mg) produced inExample 35, pyridine (31 μL), anhydrous acetic acid (24 μL) and4-dimethylaminopyridine (2 mg) were added. The reaction solution wasstirred at room temperature overnight. To the reaction solution, water(10 mL) was added. The aqueous layer was extracted twice withdichloromethane (20 mL). The combined organic layer was washed withsaturated sodium chloride solution (20 mL) and then dried over anhydrousmagnesium sulfate. After removing the anhydrous magnesium sulfate byfiltration, the filtrate was concentrated. Without purifying theresidue, the title compound (33 mg) having the following physicalproperties was obtained.

TLC: Rf 0.58 (ethyl acetate:methanol:28% aqueous ammonia=8:2:0.4);

NMR (CDCl₃): δ-0.03 (s, 18H), 0.87 (t, J=8.4 Hz, 4H), 1.00-3.75 (m,41H), 3.95-4.38 (m, 4H), 4.60-4.78 (m, 2H), 5.05-5.22 (m, 4H), 6.82-6.95(m, 4H), 7.06 (d, J=8.1 Hz, 2H), 7.20-7.35 (m, 2H).

EXAMPLE 373-(acetyl{4-[(8-cyclohexyl-2,8-diazaspiro[4.5]dec-2-yl)methyl]benzyl}amino)-2,2-bis(1H-imidazol-2-ylmethyl)propylAcetate

Except for using the compound (33 mg) produced in Example 36 in place ofthe compound produced in Example 20, the same operation as in Example 21was performed to obtain the title compound (13 mg) having the followingphysical properties.

TLC: Rf 0.22 (ethyl acetate:methanol:28% aqueous ammonia=8:2:0.4);

NMR (CDCl₃): δ 1.00-1.95 (m, 16H), 2.14 (s, 3H), 2.21 (s, 3H), 2.30-2.68(m, 15H), 3.57 (s, 2H), 3.73 (s, 2H), 4.62 (s, 2H), 6.92-7.08 (m, 6H),7.34 (d, J=8.1 Hz, 2H).

EXAMPLE 383-({4-[(8-cyclohexyl-2,8-diazaspiro[4.5]dec-2-yl)methyl]benzyl}amino)-2,2-bis(1H-imidazol-2-ylmethyl)-1-propanol

A 2N potassium hydroxide/methanol solution (2 mL) of the compound (11mg) produced in Example 37 was stirred at room temperature for 2 hours.After concentrating the reaction solution under reduced pressure, water(10 mL) was added to the residue. The aqueous layer was extracted twicewith dichloromethane (20 mL). The combined organic layer was washed withsaturated sodium chloride solution (20 mL) and then dried over anhydrousmagnesium sulfate. After removing the anhydrous magnesium sulfate byfiltration, the filtrate was concentrated. Without purifying theresidue, the title compound (8 mg) having the following physicalproperties was obtained.

TLC: Rf 0.21 (ethyl acetate:methanol:28% aqueous ammonia=8:2:0.4);

NMR (CDCl₃): δ 0.80-1.95 (m, 16H), 2.10-2.62 (m, 15H), 3.34 (m, 2H),3.59 (m, 2H), 3.77 (m, 2H), 6.93 (m, 4H), 7.22-7.38 (m, 4H).

EXAMPLE 393-hydroxy-2,2-bis[(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl)methyl]propanenitrile

A methanol (300 mL) solution of the compound (10.0 g) produced inExample 33 was cooled to 0° C. and sodium borohydride (2.13 g) wasadded. The reaction solution was stirred for 3 hours with heating toroom temperature. To the reaction solution, water (200 mL) was added.The aqueous layer was extracted twice with ethyl acetate (200 mL). Thecombined organic layer was washed with saturated sodium chloridesolution (100 mL) and then dried over anhydrous magnesium sulfate. Afterremoving the anhydrous magnesium sulfate by filtration, the filtrate wasconcentrated. The residue was purified by a medium pressure liquidchromatograph W-prep 2XY (trade name, manufactured by YAMAZENCORPORATION, column: main column 3L, inject column 3L, (n-hexane:ethylacetate=1:1→1:3→ethyl acetate:methanol: 28% aqueousammonia=95:5:0.5→90:10:1, isolation mode GR) to obtain the titlecompound (5.70 g) having the following physical properties.

TLC: Rf 0.45 (ethyl acetate:methanol:28% aqueous ammonia=9:1:0.1);

NMR (CDCl₃): δ-0.03 (s, 18H), 0.89 (dd, J=9.0, 7.2 Hz, 4H), 3.32 (s,4H), 3.48 (dd, J=10.8, 9.0 Hz, 4H), 3.85 (s, 2H), 5.31 (d, J=10.8 Hz,2H), 5.42 (d, J=10.8 Hz, 2H), 6.97 (d, J=1.2 Hz, 2H), 7.01 (J=1.2 Hz,2H).

EXAMPLE 402-formyl-3-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl)-2-[(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl)methyl]propanenitrile

Except for using the compound (475 mg) produced in Example 39 in placeof the compound produced in Example 9, the same operation as in Example10 was performed to obtain the title compound (460 mg) having thefollowing physical properties.

TLC: Rf 0.82 (ethyl acetate:methanol:28% aqueous ammonia=9:1:0.2);

NMR (CDCl₃): δ-0.03 (s, 18H), 0.80-1.00 (m, 4H), 3.40-3.70 (m, 8H),5.20-5.40 (m, 4H), 6.90-7.10 (m, 4H), 9.52 (brs, 1H).

EXAMPLE 413-({4-[(8-cyclohexyl-2,8-diazaspiro[4.5]dec-2-yl)methyl]benzyl}amino)-2,2-bis[(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl)methyl]propanenitrile

Except for using the compound (200 mg) produced in Example 40 in placeof 4-(diethoxymethyl)benzaldehyde and using1-{4-[(8-cyclohexyl-2,8-diazaspiro[4.5]dec-2-yl)methyl]phenyl}methaneamine(100 mg) in place of 8-isobutyl-2,8-diazaspiro[4.5]decane, the sameoperation as in Example 26 was performed to obtain the title compound(200 mg) having the following physical properties.

TLC: Rf 0.55 (ethyl acetate:methanol:28% aqueous ammonia=8:2:0.4);

NMR (CDCl₃): δ-0.03 (s, 18H), 0.80-0.98 (m, 4H), 1.00-1.92 (m, 16H),1.95-2.60 (m, 11H), 3.20-3.60 (m, 10H), 3.84 (s, 2H), 5.27 (d, J=10.8Hz, 2H), 5.40 (d, J=10.8 Hz, 2H), 6.96-7.02 (m, 4H), 7.18-7.35 (m, 4H).

EXAMPLE 423-({4-[(8-cyclohexyl-2,8-diazaspiro[4.5]dec-2-yl)methyl]benzyl}amino)-2,2-bis(1H-imidazol-2-ylmethyl)propanenitrile

An aqueous 95% trifluoroacetic acid solution (2.2 mL) of the compound(100 mg) produced in Example 41 was stirred at 50° C. for 4 hours.Subsequently, methanol (2 mL) and 5N hydrochloric acid (2 mL) wereadded, followed by stirring at 50° C. for 2 days. The reaction solutionwas concentrated under reduced pressure. The residue was purified bysilica gel chromatography (ethyl acetate:methanol: 28% aqueousammonia=8:2:0→0.4) to obtain the title compound (20 mg) having thefollowing physical properties.

TLC: Rf 0.76 (ethyl acetate:methanol:28% aqueous ammonia=8:2:0.5);

NMR (CDCl₃): δ 1.00-1.35 (m, 6H), 1.52-1.95 (m, 10H), 2.30 (m, 1H), 2.36(s, 2H), 2.42-2.60 (m, 4H), 2.58 (t, J=6.9 Hz, 2H), 2.69 (s, 2H), 2.97(s, 4H), 3.58 (s, 2H), 3.87 (s, 2H), 7.02 (s, 4H), 7.30 (s, 4H).

EXAMPLE 433-(methoxymethoxy)-2,2-bis[(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl)methyl]propanenitrile

To a dimethylformamide (5 mL) suspension of sodium hydride (22 mg), adimethylformamide (5 mL) solution of the compound (500 mg) produced inExample 39 was added. The reaction solution was stirred at 50° C. for 30minutes. The reaction solution was cooled to room temperature andchloromethylmethylether (150 μL) was added. The reaction solution wasstirred at room temperature for 2 hours. To the reaction solution, water(10 mL) was added, followed by extraction twice with dichloromethane (20mL). The combined organic layer was washed with saturated sodiumchloride solution (20 mL) and then dried over anhydrous magnesiumsulfate. After removing the anhydrous magnesium sulfate by filtration,the filtrate was concentrated. The residue was purified by silica gelchromatography (n-hexane:ethyl acetate=1:1→1:3→ethyl acetate:methanol:28% aqueous ammonia=95:5:0.5→90:10:1) to obtain the title compound (310mg) having the following physical properties.

TLC: Rf 0.65 (ethyl acetate:methanol:28% aqueous ammonia=19:1:0.1);

NMR (CDCl₃): δ-0.03 (s, 18H), 0.87 (m, 4H), 3.30-3.60 (m, 11H), 3.98 (s,2H), 4.73 (s, 2H), 5.29 (d, J=10.8 Hz, 2H), 5.35 (d, J=10.8 Hz, 2H),6.97 (d, J=1.5 Hz, 2H), 7.01 (d, J=1.5 Hz, 2H).

EXAMPLE 443-(methoxymethoxy)-2,2-bis[(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl)methyl]-1-propanamine

Except for using the compound (880 mg) produced in Example 43, the sameoperation as in Example 18 was performed to obtain the title compound(870 mg) having the following physical properties.

TLC: Rf 0.69 (ethyl acetate:methanol:28% aqueous ammonia=8:2:0.2);

NMR (CDCl₃): δ-0.03 (s, 18H), 0.88 (t, J=8.4 Hz, 4H), 2.80 (s, 2H), 2.85(d, J=15.3 Hz, 2H), 2.96 (d, J=15.3 Hz, 2H), 3.28 (s, 3H), 3.35-3.62 (m,6H), 4.57 (s, 2H), 5.24 (d, J=10.8 Hz, 2H), 5.36 (d, J=10.8 Hz, 2H),6.89 (d, J=1.5 Hz, 2H), 6.97 (d, J=1.5 Hz, 2H).

EXAMPLE 45N-{4-[(8-isobutyl-2,8-diazaspiro[4.5]dec-2-yl)methyl]benzyl}-3-(methoxymethoxy)-2,2-bis[(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl)methyl]-1-propanamine

Except for using the compound (350 mg) produced in Example 44 in placeof 8-isobutyl-2,8-diazaspiro[4.5]decane and using the compound (247 mg)produced in Example 27 in place of 4-(diethoxymethyl)benzaldehyde, thesame operation as in Example 26 was performed to obtain the titlecompound (320 mg) having the following physical properties.

TLC: Rf 0.73 (ethyl acetate:methanol:28% aqueous ammonia=19:1:0.1);

NMR (CDCl₃): δ-0.03 (s, 18H), 0.80-0.98 (m, 4H), 0.87 (d, J=6.6 Hz, 6H),1.48-1.85 (m, 7H), 2.02 (d, J=7.2 Hz, 2H), 2.20-2.65 (m, 10H), 2.91 (d,J=15.0 Hz, 2H), 2.99 (d, J=15.0 Hz, 2H), 3.24 (s, 3H), 3.42 (t, J=8.4Hz, 4H), 3.51 (s, 2H), 3.55 (s, 2H), 3.70 (s, 2H), 4.55 (s, 2H), 5.27(d, J=10.8 Hz, 2H), 5.37 (d, J=10.8 Hz, 2H), 6.88 (d, J=1.2 Hz, 2H),6.95 (d, J=1.2 Hz, 2H), 7.20-7.35 (m, 4H).

EXAMPLE 463-(1H-imidazol-2-yl)-2-(1H-imidazol-2-ylmethyl)-2-[({4-[(8-isobutyl-2,8-diazaspiro[4.5]dec-2-yl)methyl]benzyl}amino)methyl]-1-propanol

An aqueous 95% trifluoroacetic acid solution (2.2 mL) solution of thecompound (84 mg) produced in Example 45 was stirred at 50° C. for 4hours. The reaction solution was concentrated under reduced pressure. Tothe residue, 6N hydrochloric acid (10 mL) was added, followed bystirring at 90° C. for 22 hours. The reaction solution was concentratedunder reduced pressure. The residue was purified by silica gelchromatography (n-hexane:ethyl acetate=1:3 ethyl acetate:methanol: 28%aqueous ammonia=100:0:0→100:10:1) to obtain the title compound (48 mg)having the following physical properties.

TLC: Rf 0.51 (ethyl acetate:methanol:28% aqueous ammonia=8:2:0.4);

NMR (CDCl₃): δ 0.87 (d, J=6.6 Hz, 6H), 1.50-1.70 (m, 6H), 1.78 (m, 1H),2.02 (d, J=7.2 Hz, 2H), 2.20-2.62 (m, 14H), 3.33 (s, 2H), 3.58 (s, 2H),3.77 (s, 2H), 6.92 (s, 4H), 7.20-7.40 (m, 4H).

EXAMPLE 47N-{4-[(8-isobutyl-2,8-diazaspiro[4.5]dec-2-yl)methyl]benzyl}-3-(methoxymethoxy)-N-methyl-2,2-bis[(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl)methyl]-1-propanamine

Except for using the compound (75 mg) produced in Example 45 in place ofthe compound produced in Example 20, the same operation as in Example 22was performed to obtain the title compound (56 mg) having the followingphysical properties.

TLC: Rf 0.77 (ethyl acetate:methanol:28% aqueous ammonia=9:1:0.1);

NMR (CDCl₃): δ-0.03 (s, 18H), 0.80-0.98 (m, 4H), 0.87 (d, J=6.6 Hz, 6H),1.48-1.85 (m, 7H), 1.98-2.08 (m, 2H), 2.15-2.62 (m, 13H), 2.90-3.80 (m,17H), 4.57 (s, 2H), 5.13 (d, J=10.8 Hz, 2H), 5.19 (d, J=10.8 Hz, 2H),6.85 (s, 2H), 6.95 (s, 2H), 7.18-7.40 (m, 4H).

EXAMPLE 483-(1H-imidazol-2-yl)-2-(1H-imidazol-2-ylmethyl)-2-{[{4-[(8-isobutyl-2,8-diazaspiro[4.5]dec-2-yl)methyl]benzyl}(methyl)amino]methyl}-1-propanol

An aqueous 95% trifluoroacetic acid solution (2.2 mL) of the compound(56 mg) produced in Example 47 was stirred at 50° C. for one hour.Subsequently, methanol (3 mL) and concentrated hydrochloric acid (3 mL)were added, followed by stirring at 50° C. for 3 hours. The reactionsolution was concentrated under reduced pressure. The residue waspurified by silica gel chromatography (ethyl acetate:methanol: 28%aqueous ammonia=8:2:0→0.2) to obtain the title compound (17 mg) havingthe following physical properties.

TLC: Rf 0.38 (ethyl acetate:methanol:28% aqueous ammonia=8:2:0.4);

NMR (CDCl₃): δ 0.87 (d, J=6.6 Hz, 6H), 1.45-1.90 (m, 7H), 2.01 (d, J=7.5Hz, 2H), 2.16-2.80 (m, 17H), 3.30 (s, 2H), 3.56 (s, 4H), 7.00 (s, 4H),7.22-7.38 (m, 4H).

EXAMPLE 48(1)3-[{4-[(8-cyclohexyl-2,8-diazaspiro[4.5]dec-2-yl)methyl]benzyl}(methyl)amino]-2,2-bis(1H-imidazol-2-ylmethyl)propanenitrile

Except for using the compound (50 mg) produced in Example 41 in place ofthe compound produced in Example 20, the same operation as in Example22→Example 21 was performed to obtain the title compound (9 mg) havingthe following physical properties.

TLC: Rf 0.57 (ethyl acetate:methanol:28% aqueous ammonia=8:2:0.5);

NMR (CDCl₃): δ 1.00-1.35 (m, 6H), 1.52-1.92 (m, 10H), 2.22 (m, 1H), 2.35(s, 2H), 2.40-2.58 (m, 4H), 2.45 (s, 3H), 2.54 (t, J=7.2 Hz, 2H), 2.74(s, 2H), 2.80 (d, J=14.4 Hz, 2H), 3.07 (d, J=14.4 Hz, 2H), 3.55 (s, 2H),3.68 (s, 2H), 7.04 (s, 4H), 7.24 (s, 4H), 11.3 (brs, 2H).

EXAMPLE 49N-{4-[(8-isobutyl-2,8-diazaspiro[4.5]dec-2-yl)methyl]benzyl}-N-{3-(methoxymethoxy)-2,2-bis[(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl)methyl]propyl}acetamide

Except for using the compound (100 mg) produced in Example 45 in placeof the compound produced in Example 35, the same operation as in Example36 was performed to obtain the title compound (75 mg) having thefollowing physical properties.

TLC: Rf 0.65 (ethyl acetate:methanol:28% aqueous ammonia=9:1:0.1);

NMR (CDCl₃): δ-0.03 (s, 18H), 0.80-0.98 (m, 10H), 1.50-2.75 (m, 20H),2.95-3.78 (m, 15H), 3.90-4.10 (m, 2H), 4.52-4.63 (m, 2H), 4.68-4.72 (m,2H), 5.00-5.28 (m, 4H), 6.80-6.98 (m, 4H), 7.00-7.38 (m, 4H).

EXAMPLE 50N-[3-hydroxy-2,2-bis(1H-imidazol-2-ylmethyl)propyl]-N-{4-[(8-isobutyl-2,8-diazaspiro[4.5]dec-2-yl)methyl]benzyl}acetamide

An aqueous 95% trifluoroacetic acid solution (2.2 mL) of the compound(75 mg) produced in Example 49 was stirred at 50° C. for one hour. Thereaction solution was concentrated under reduced pressure. The residuewas purified by silica gel chromatography (ethyl acetate:methanol:=10:0→10:1) to obtain the title compound (40 mg) having the followingphysical properties.

TLC: Rf 0.72 (ethyl acetate:methanol:28% aqueous ammonia=8:2:0.4);

NMR (DMSO-d₆): δ 0.85 (d, J=6.6 Hz, 6H), 1.45-1.58 (m, 6H), 1.73 (m,1H), 1.98-2.05 (m, 5H), 2.22-2.68 (m, 12H), 3.22 (s, 2H), 3.40 (s, 2H),3.54 (s, 2H), 4.80 (s, 2H), 6.94 (s, 4H), 7.08 (d, J=8.1 Hz, 2H), 7.25(d, J=8.1 Hz, 2H).

EXAMPLE 50(1)N-[2-cyano-3-(1H-imidazol-2-yl)-2-(1H-imidazol-2-ylmethyl)propyl]-N-{4-[(8-cyclohexyl-2,8-diazaspiro[4.5]dec-2-yl)methyl]benzyl}acetamide

Except for using the compound (50 mg) produced in Example 41 in place ofthe compound produced in Example 35, the same operation as in Example36→Example 21 was performed to obtain the title compound (10 mg) havingthe following physical properties.

TLC: Rf 0.51 (ethyl acetate:methanol:28% aqueous ammonia=8:2:0.5);

NMR (CDCl₃): δ 1.00-1.38 (m, 6H), 1.52-1.95 (m, 10H), 2.27 (m, 1H), 2.30(s, 3H), 2.35 (s, 2H), 2.40-2.58 (m, 4H), 2.55 (t, J=6.6 Hz, 2H), 2.85(d, J=14.4 Hz, 2H), 3.03 (d, J=14.4 Hz, 2H), 3.53 (brs, 2H), 3.57 (s,2H), 5.00 (s, 2H), 7.07 (d, J=7.8 Hz, 2H), 7.09 (s, 4H), 7.34 (d, J=7.8Hz, 2H), 12.7 (brs, 2H).

EXAMPLE 51ethyl({4-[(8-cyclohexyl-2,8-diazaspiro[4.5]dec-2-yl)methyl]benzyl}amino)acetate

To an ethanol solution (2 mL) of1-{4-[(8-cyclohexyl-2,8-diazaspiro[4.5]dec-2-yl)methyl]phenyl}methaneamine(132 mg) and a toluene solution (93 μL) of 50% ethyl oxoacetate, 10%palladium carbon (30 mg) was added and the atmosphere in the reactionsystem was replaced by hydrogen. The reaction solution was stirred atroom temperature for 6 hours. After palladium carbon was removed byfiltering the reaction solution through Celite (trade name), thefiltrate was concentrated. Without purifying the residue, the titlecompound (200 mg) having the following physical properties was obtained.

TLC: Rf 0.53 (ethyl acetate:methanol:28% aqueous ammonia=8:2:0.4);

NMR (CDCl₃): δ 1.00-2.00 (m, 19H), 2.10-2.68 (m, 9H), 3.41 (s, 2H), 3.56(s, 2H), 3.78 (s, 2H), 4.08-4.22 (m, 2H), 7.08-7.35 (m, 4H).

EXAMPLE 522-({4-[(8-cyclohexyl-2,8-diazaspiro[4.5]dec-2-yl)methyl]benzyl}amino)ethanol

Except for using the compound (100 mg) produced in Example 51 in placeof the compound produced in Example 5, the same operation as in Example18 was performed to obtain the title compound the title compound (64 mg)having the following physical properties.

TLC: Rf 0.18 (ethyl acetate:methanol:28% aqueous ammonia=8:2:0.4);

NMR (CDCl₃): δ 1.00-1.98 (m, 16H), 2.12-2.60 (m, 9H), 2.82 (dd, J=5.7,4.8 Hz, 2H), 3.56 (s, 2H), 3.58-3.70 (m, 2H), 3.79 (s, 2H), 7.08-7.35(m, 4H).

EXAMPLE 532-({4-[(8-cyclohexyl-2,8-diazaspiro[4.5]dec-2-yl)methyl]benzyl}{3-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl)-2-[(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl)methyl]propyl}amino)ethanol

Except for using the compound (64 mg) produced in Example 52 in place of8-isobutyl-2,8-diazaspiro[4.5]decane and using the compound (90 mg)produced in Example 19 in place of 4-(diethoxymethyl)benzaldehyde, thesame operation as in Example 26 was performed to obtain the titlecompound (75 mg) having the following physical properties.

TLC: Rf 0.65 (ethyl acetate:methanol:28% aqueous ammonia=8:2:0.4);

NMR (CDCl₃): δ-0.03 (s, 18H), 0.88-0.95 (m, 4H), 1.00-1.92 (m, 16H),2.10-3.00 (m, 18H), 3.32-3.70 (m, 10H), 5.08 (s, 4H), 6.80-7.00 (m, 4H),7.04-7.30 (m, 4H).

EXAMPLE 542-{{4-[(8-cyclohexyl-2,8-diazaspiro[4.5]dec-2-yl)methyl]benzyl}[3-(1H-imidazol-2-yl)-2-(1H-imidazol-2-ylmethyl)propyl]amino}ethanol

Except for using the compound (38 mg) produced in Example 53 in place ofthe compound produced in Example 20, the same operation as in Example 21was performed to obtain the title compound (15 mg) having the followingphysical properties.

TLC: Rf 0.30 (ethyl acetate:methanol:28% aqueous ammonia=8:2:0.4);

NMR (CDCl₃): δ 1.00-1.35 (m, 6H), 1.50-1.92 (m, 10H), 2.18-2.70 (m,16H), 2.74 (dd, J=14.1, 7.5 Hz, 2H), 3.57 (s, 2H), 3.59 (s, 2H), 3.64(t, J=5.4 Hz, 2H), 6.97 (s, 4H), 7.29 (s, 4H).

EXAMPLE 552-({4-[(8-cyclohexyl-2,8-diazaspiro[4.5]dec-2-yl)methyl]benzyl}{3-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl)-2-[(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl)methyl]propyl}amino)ethylAcetate

Except for using the compound (38 mg) produced in Example 53 in place ofthe compound produced in Example 35, the same operation as in Example 36was performed to obtain the title compound (38 mg) having the followingphysical properties.

TLC: Rf 0.62 (ethyl acetate:methanol:28% aqueous ammonia=8:2:0.4);

NMR (CDCl₃): δ-0.03 (s, 18H), 0.88-1.00 (m, 4H), 1.00-3.10 (m, 37H),3.38-3.90 (m, 8H), 4.00-4.18 (m, 2H), 5.10-5.32 (m, 4H), 6.78-6.95 (m,4H), 7.00-7.38 (m, 4H).

EXAMPLE 562-({4-[(8-cyclohexyl-2,8-diazaspiro[4.5]dec-2-yl)methyl]benzyl}[3-(1H-imidazol-2-yl)-2-(1H-imidazol-2-ylmethyl)propyl]amino)ethylAcetate

Except for using the compound (38 mg) produced in Example 55 in place ofthe compound produced in Example 20, the same operation as in Example 21was performed to obtain the title compound (6 mg) having the followingphysical properties.

TLC: Rf 0.62 (ethyl acetate:methanol:28% aqueous ammonia=8:2:0.4);

NMR (CDCl₃): δ 1.05-2.90 (m, 32H), 2.05 (s, 3H), 2.77 (t, J=6.0 Hz, 2H),3.59 (s, 2H), 3.61 (s, 2H), 4.23 (t, J=6.0 Hz, 2H), 6.87 (s, 4H),7.25-7.38 (m, 4H).

EXAMPLE 57N-{4-[(8-cyclohexyl-2,8-diazaspiro[4.5]dec-2-yl)methyl]benzyl}-3-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl)-2-[(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl)methyl]-1-propanamine

Except for using the compound (164 mg) produced in Example 19 in placeof 4-(diethoxymethyl)benzaldehyde and using1-{4-[(8-cyclohexyl-2,8-diazaspiro[4.5]dec-2-yl)methyl]phenyl}methaneamine(100 mg) in place of 8-isobutyl-2,8-diazaspiro[4.5]decane, the sameoperation as in Example 26 was performed to obtain the title compound(220 mg) having the following physical properties.

TLC: Rf 0.42 (ethyl acetate:methanol:28% aqueous ammonia=8:2:0.2);

NMR (CDCl₃): δ-0.03 (s, 18H), 0.87 (t, J=8.4 Hz, 4H), 1.00-1.95 (m,16H), 2.12-2.95 (m, 16H), 3.40-3.50 (m, 4H), 3.54 (s, 2H), 3.70 (s, 2H),5.19 (d, J=10.8 Hz, 2H), 5.27 (d, J=10.8 Hz, 2H), 6.88 (d, J=1.5 Hz,2H), 6.92 (d, J=1.5 Hz, 2H), 7.18-7.28 (m, 4H).

EXAMPLE 58ethyl({4-[(8-cyclohexyl-2,8-diazaspiro[4.5]dec-2-yl)methyl]benzyl}{3-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl)-2-[(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl)methyl]propyl}amino)acetate

To a 10% acetic acid-dimethylformamide (2.2 mL) solution of the compound(125 mg) produced in Example 57 and a 50% ethyl glyoxylate/toluenesolution (148 μL), sodium triacetoxyborohydride (337 mg) was added. Thereaction solution was stirred at room temperature for 17 hours. 1Nhydrochloric acid was added to the reaction solution so as to adjust thepH to about 5. The aqueous layer was extracted twice withdichloromethane (20 mL). The combined organic layer was washed withsaturated sodium chloride solution (20 mL) and then dried over anhydrousmagnesium sulfate. After removing the anhydrous magnesium sulfate byfiltration, the filtrate was concentrated. The residue was purified bysilica gel chromatography (n-hexane:ethyl acetate=1:1→0:1→ethylacetate:methanol=100:0→30:1) to obtain the title compound (53 mg) havingthe following physical properties.

TLC: Rf 0.78 (ethyl acetate:methanol:28% aqueous ammonia=8:2:0.2);

NMR (CDCl₃): δ d-0.03 (s, 18H), 0.87 (t, J=8.1 Hz, 4H), 1.00-1.90 (m,16H), 1.23 (t, J=7.2 Hz, 3H), 2.12-2.68 (m, 12H), 2.72-2.82 (m, 2H),2.88-3.00 (m, 2H), 3.26 (s, 2H), 3.44 (t, J=8.1 Hz, 4H), 3.53 (s, 2H),3.70 (s, 2H), 4.09 (q, J=7.2 Hz, 2H), 5.15 (d, J=10.8 Hz, 2H), 5.24 (d,J=10.8 Hz, 2H), 6.87 (d, J=1.5 Hz, 2H), 6.89 (d, J=1.5 Hz, 2H), 7.21 (s,4H).

EXAMPLE 59ethyl({4-[(8-cyclohexyl-2,8-diazaspiro[4.5]dec-2-yl)methyl]benzyl}[3-(1H-imidazol-2-yl)-2-(1H-imidazol-2-ylmethyl)propyl]amino)acetate

Except for using the compound (52 mg) produced in Example 58 in place ofthe compound produced in Example 20, the same operation as in Example 21was performed to obtain the title compound (38 mg) having the followingphysical properties.

TLC: Rf 0.34 (ethyl acetate:methanol:28% aqueous ammonia=8:2:0.4);

NMR (CDCl₃): δ 1.00-1.36 (m, 6H), 1.24 (t, J=7.2 Hz, 3H), 1.48-1.92 (m,10H), 2.18-2.55 (m, 10H), 2.58 (t, J=6.9 Hz, 2H), 2.60-2.80 (m, 4H),3.26 (s, 2H), 3.57 (s, 2H), 3.62 (s, 2H), 4.15 (q, J=7.2 Hz, 2H), 6.99(m, 4H), 7.31 (m, 4H), 11.8 (brs, 2H).

EXAMPLE 60({4-[(8-cyclohexyl-2,8-diazaspiro[4.5]dec-2-yl)methyl]benzyl}[3-(1H-imidazol-2-yl)-2-(1H-imidazol-2-ylmethyl)propyl]amino)aceticAcid

To the compound (28 mg) produced in Example 59, concentratedhydrochloric acid (2 mL) was added, followed by stirring at 90° C. for 6hours. The reaction solution was azeotroped with toluene. The residuewas purified by silica gel chromatography (manufactured by FUJI SILYSIACHEMICAL LTD., CHROMATOREX NH (trade name)(dichloromethane:methanol=10:0→7:3) to obtain the title compound (13 mg)having the following physical properties.

TLC: Rf 0.35 (dichloromethane:methanol:28% aqueous ammonia=8:2:0.5);

NMR (CD₃OD): δ 1.04-2.05 (m, 16H), 2.30-2.95 (m, 16H), 3.00 (s, 2H),3.58 (s, 2H), 3.59 (s, 2H), 6.94 (s, 4H), 7.22 (d, J=8.4 Hz, 2H), 7.26(d, J=8.4 Hz, 2H).

EXAMPLE 61N-(2-methoxyethyl)-3-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl)-2-[(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl)methyl]-1-propanamine

Except for using the compound (120 mg) produced in Example 19 and using2-methoxyethylamine (39 mg) in place of8-isobutyl-2,8-diazaspiro[4.5]decane, the same operation as in Example26 was performed to obtain the title compound (107 mg) having thefollowing physical properties.

TLC: Rf 0.49 (ethyl acetate:methanol:28% aqueous ammonia=8:2:0.2);

NMR (CDCl₃): δ-0.03 (s, 18H), 0.87 (t, J=8.1 Hz, 4H), 2.58 (m, 1H), 2.64(d, J=5.7 Hz, 2H), 2.72 (t, J=5.4 Hz, 2H), 2.80-2.98 (m, 4H), 3.32 (s,3H), 3.40-3.48 (m, 6H), 5.19 (d, J=10.8 Hz, 2H), 5.29 (d, J=10.8 Hz,2H), 6.88 (s, 2H), 6.91 (s, 2H).

EXAMPLE 62N-{4-[(8-cyclohexyl-2,8-diazaspiro[4.5]dec-2-yl)methyl]benzyl}-N-(2-methoxyethyl)-3-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl)-2-[(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl)methyl]-1-propanamine

Except for using the compound (55 mg) produced in Example 61 in place of8-isobutyl-2,8-diazaspiro[4.5]decane and using (43 mg) in place of4-(diethoxymethyl)benzaldehyde, the same operation as in Example 26 wasperformed to obtain the title compound (50 mg) having the followingphysical properties.

TLC: Rf 0.56 (ethyl acetate:methanol:28% aqueous ammonia=8:2:0.2);

NMR (CDCl₃): δ-0.03 (s, 18H), 0.80-0.95 (m, 4H), 1.00-1.95 (m, 16H),2.18-2.95 (m, 18H), 3.22-3.65 (m, 13H), 5.10-5.32 (m, 4H), 6.82-6.95 (m,4H), 7.19 (s, 4H).

EXAMPLE 63N-{4-[(8-cyclohexyl-2,8-diazaspiro[4.5]dec-2-yl)methyl]benzyl}-3-(1H-imidazol-2-yl)-2-(1H-imidazol-2-ylmethyl)-N-(2-methoxyethyl)-1-propanamine

Except for using the compound (50 mg) produced in Example 62 in place ofthe compound produced in Example 20, the same operation as in Example 21was performed to obtain the title compound (12 mg) having the followingphysical properties.

TLC: Rf 0.52 (ethyl acetate:methanol:28% aqueous ammonia=8:2:0.4);

NMR (CDCl₃): δ 0.80-1.94 (m, 16H), 2.20-2.75 (m, 18H), 3.32 (s, 3H),3.42 (t, J=5.1 Hz, 2H), 3.57 (s, 2H), 3.59 (s, 2H), 6.96 (s, 4H), 7.28(s, 4H).

EXAMPLE 63(1)-EXAMPLE 63(2)

Except for using the corresponding amine in place of 2-methoxyethylamineand using the corresponding aldehyde in place of the compound producedin Example 19 in Example 61, the same operation as in Example 61→Example62→Example 63 was performed to obtain the following compounds.

EXAMPLE 63(1)N-{4-[(8-cyclohexyl-2,8-diazaspiro[4.5]dec-2-yl)methyl]benzyl}-3-(1H-imidazol-2-yl)-2-(1H-imidazol-2-ylmethyl)-N-[2-(1-pyrrolidinyl)ethyl]-1-propanamine

TLC: Rf 0.35 (ethyl acetate:methanol:28% aqueous ammonia=8:2:0.4);

NMR (CDCl₃): δ 0.80-2.03 (m, 20H), 2.20-2.82 (m, 24H), 3.48 (s, 2H),3.57 (s, 2H), 6.98 (s, 4H), 7.24 (s, 4H).

EXAMPLE 63(2)N-[3-(1H-imidazol-2-yl)-2-(1H-imidazol-2-ylmethyl)propyl]-N-{4-[(8-isobutyl-2,8-diazaspiro[4.5]dec-2-yl)methyl]benzyl}-1,2-ethanediamine

TLC: Rf 0.38 (ethyl acetate:methanol:28% aqueous ammonia=8:2:0.4);

NMR (CDCl₃): δ 0.87 (d, J=6.3 Hz, 6H), 1.45-1.70 (m, 6H), 1.77 (m, 1H),2.04 (d, J=7.2 Hz, 2H), 2.20-2.85 (m, 19H), 3.54 (s, 2H), 3.57 (s, 2H),6.98 (s, 4H), 7.18-7.38 (m, 4H).

EXAMPLE 64 2-formyl-N,N-dimethyl-1H-imidazole-1-sulfonamide

To an acetonitrile (500 mL) solution of 2-formylimidazole (64 g) andtriethylamine (140 mL), dimethylsulfamoyl chloride (100 g) was added atroom temperature. The reaction solution was stirred at 50° C. for 16hours. The reaction solution was cooled to room temperature and theprecipitated crystal was removed by filtration, and then the filtratewas concentrated under reduced pressure. The residue was washed withethyl acetate to obtain a crude compound. The wash solution was washedwith saturated sodium chloride solution and then dried over anhydroussodium sulfate. After removing the anhydrous sodium sulfate byfiltration, the filtrate was concentrated. The residue was purified bysilica gel chromatography (ethyl acetate) to obtain a crude product. Thecrude product was combined with the crude product obtained previously,followed by washing with ether to obtain the title compound (88.3 g)having the following physical properties.

TLC: Rf 0.69 (Chloroform:methanol=9:1);

NMR (CDCl₃): δ 3.02 (s, 6H), 7.32 (d, J=1.3 Hz, 1H), 7.59 (dd, J=1.3,0.8 Hz, 1H), 9.95 (d, J=0.8 Hz, 1H).

EXAMPLE 65 2-(hydroxymethyl)-N,N-dimethyl-1H-imidazole-1-sulfonamide

A methanol (5 mL) solution of the compound (470 mg) produced in Example64 was cooled to 0° C. and sodium borohydride (87.8 mg) was added. Afterstirring the reaction solution at 0° C. for 30 minutes, water was added.The reaction solution was concentrated under reduced pressure, extractedwith ethyl acetate. Then the organic layer was dried over anhydroussodium sulfate and concentrated under reduced pressure. The precipitatedpowder was washed with ether to obtain the title compound (367 mg)having the following physical properties.

TLC: Rf 0.63 (dichloromethane: methanol=9:1);

NMR (CDCl₃): δ 2.94 (s, 6H), 4.87 (s, 2H), 7.02 (d, J=1.5 Hz, 1H), 7.26(d, J=1.5 Hz, 1H).

EXAMPLE 66 2-(chloromethyl)-N,N-dimethyl-1H-imidazole-1-sulfonamide

To a tetrahydrofuran (100 mL) solution of the compound (15.0 g) producedin Example 65, triethylamine (20 mL) was added, followed by cooling to0° C. Methanesulfonyl chloride (7.03 mL) and lithium chloride (9.30 g)were added. The reaction solution was stirred for 3 hours with heatingto room temperature. To the reaction solution, water (100 mL) was added.The aqueous layer was extracted twice with ethyl acetate (100 mL). Thecombined organic layer was washed with saturated sodium chloridesolution (50 mL) and then dried over anhydrous magnesium sulfate. Afterremoving the anhydrous magnesium sulfate by filtration, the filtrate wasconcentrated. Without purifying the residue, the title compound (15.7 g)having the following physical properties was obtained.

TLC: Rf 0.85 (ethyl acetate:methanol=19:1);

NMR (CDCl₃): δ 3.00 (s, 6H), 4.91 (s, 2H), 7.09 (d, J=1.5 Hz, 1H), 7.28(d, J=1.5 Hz, 1H).

EXAMPLE 67 Diethylbis({1-[(dimethylamino)sulfonyl]-1H-imidazol-2-yl}methyl)malonate

Except for using the compound (13.0 mg) produced in Example 66 in placeof the compound produced in Example 3, the same operation as in Example4 was performed to obtain the title compound (12.8 g) having thefollowing physical properties.

TLC: Rf 0.17 (n-hexane:ethyl acetate:methanol=1:2);

NMR (CDCl₃): δ 1.17 (t, J=7.2 Hz, 6H), 2.86 (s, 12H), 4.00 (s, 4H), 4.20(q, J=7.2 Hz, 4H), 6.86 (d, J=1.5 Hz, 2H), 7.19 (d, J=1.5 Hz, 2H).

EXAMPLE 683-{1-[(dimethylamino)sulfonyl]-1H-imidazol-2-yl}-2-({1-[(dimethylamino)sulfonyl]-1H-imidazol-2-yl}methyl)propanoicAcid

Except for using the compound (5.98 mg) produced in Example 67 in placeof the compound produced in Example 4, the same operation as in Example5 was performed to obtain the title compound (1.50 g) having thefollowing physical properties.

TLC: Rf 0.35 (dichloromethane:methanol:28% aqueous ammonia=8:2:0.5);

NMR (CDCl₃): δ 2.94 (s, 12H), 3.26-3.45 (m, 4H), 3.82 (m, 1H), 6.94 (d,J=1.5 Hz, 2H), 7.02 (d, J=1.5 Hz, 2H).

EXAMPLE 69benzyl[2-{1-[(dimethylamino)sulfonyl]-1H-imidazol-2-yl}-1-({1-[(dimethylamino)sulfonyl]-1H-imidazol-2-yl}methyl)ethyl]carbamate

A benzyl alcohol (4 mL) solution of the compound (567 mg) produced inExample 68, triethylamine (643 μL) and diphenyl phosphorylazide (527 μL)were added. The reaction solution was stirred at 85° C. for 8 hours. Tothe reaction solution, water (20 mL) was added. The aqueous layer wasextracted twice with ethyl acetate (20 mL). The combined organic layerwas washed with saturated sodium chloride solution (20 mL) and thendried over anhydrous magnesium sulfate. After removing the anhydrousmagnesium sulfate by filtration, the filtrate was concentrated. Theresidue was purified by silica gel chromatography (n-hexane:ethylacetate=1:1→0:1→ethyl acetate:methanol: 28% aqueousammonia=20:1:0.2→10:1:0.1) to obtain the title compound (472 mg) havingthe following physical properties.

TLC: Rf 0.40 (ethyl acetate:methanol:28% aqueous ammonia=9:1:0.2);

NMR (CDCl₃): δ 2.82 (s, 12H), 3.20-3.40 (m, 4H), 4.71 (m, 1H), 5.03 (s,2H), 6.55 (m, 1H), 6.84-7.00 (m, 4H), 7.02-7.38 (m, 5H).

EXAMPLE 702,2′-(2-amino-1,3-propanyl)bis(N,N-dimethyl-1H-imidazole-1-sulfonamide)

To an ethanol solution (5 mL) of the compound (470 mg) produced inExample 69, 10% palladium carbon (100 mg) was added and the atmospherein the reaction system was replaced by hydrogen. The reaction solutionwas stirred at room temperature for 8 hours. After removing palladiumcarbon by filtering the reaction solution through Celite (trade name),the filtrate was concentrated. The residue was purified by silica gelchromatography (n-hexane:ethyl acetate=1:1→ethyl acetate:methanol: 28%aqueous ammonia=100:0:0→80:20:2) to obtain the title compound (160 mg)having the following physical properties.

TLC: Rf 0.50 (ethyl acetate:methanol:28% aqueous ammonia=8:1:0.5);

NMR (CDCl₃): δ 2.86 (s, 12H), 3.22-3.40 (m, 4H), 4.03 (m, 1H), 6.95 (d,J=1.5 Hz, 2H), 7.22 (d, J=1.5 Hz, 2H).

EXAMPLE 71 4-(hydroxymethyl)cyclohexanol

Except for using ethyl 4-oxocyclohexanecarboxylate (1.00 g) in place ofthe compound produced in Example 5, the same operation as in Example 18was performed to obtain the title compound (1.00 g) having the followingphysical properties.

TLC: Rf 0.16 (n-hexane:ethyl acetate=1:3);

NMR (CDCl₃): δ 0.92-2.10 (m, 9H), 3.40-3.62 (m, 2H), 4.01 (m, 1H).

EXAMPLE 72 4-oxocyclohexanecarbaldehyde

Except for using the compound (1.00 mg) produced in Example 71 in placeof the compound produced in Example 9, the same operation as in Example10 was performed to obtain the title compound (1.00 g) having thefollowing physical properties.

TLC: Rf 0.31 (n-hexane:ethyl acetate=1:1);

NMR (CDCl₃): δ 1.65-2.50 (m, 8H), 2.66 (m, 1H), 9.76 (s, 1H).

EXAMPLE 734-[(8-cyclohexyl-2,8-diazaspiro[4.5]dec-2-yl)methyl]cyclohexanone

Except for using the compound (550 mg) produced in Example 72 in placeof 4-(diethoxymethyl)benzaldehyde and using8-cyclohexyl-2,8-diazaspiro[4.5]decane (295 mg) in place of8-isobutyl-2,8-diazaspiro[4.5]decane, the same operation as in Example26 was performed to obtain the title compound (100 mg) having thefollowing physical properties.

TLC: Rf 0.55 (ethyl acetate:methanol:28% aqueous ammonia=8:2:0.4);

NMR (CDCl₃): δ 0.82-2.00 (m, 21H), 2.00-2.60 (m, 15H).

EXAMPLE 742,2′-[2-({4-[(8-cyclohexyl-2,8-diazaspiro[4.5]dec-2-yl)methyl]cyclohexyl}amino)-1,3-propanyl]bis(N,N-dimethyl-1H-imidazole-1-sulfonamide)

Except for using the compound (90 mg) produced in Example 73 in place of4-(diethoxymethyl)benzaldehyde and using the compound (143 mg) producedin Example 70 in place of 8-isobutyl-2,8-diazaspiro[4.5]decane, the sameoperation as in Example 26 was performed to obtain the title compound(100 mg) having the following physical properties.

TLC: Rf 0.43 (ethyl acetate:methanol:28% aqueous ammonia=8:2:0.5);

NMR (CD₃OD): δ 0.80-2.05 (m, 25H), 2.25-2.95 (m, 12H), 2.86 (s, 12H),3.02-3.22 (m, 4H), 3.58 (m, 1H), 6.94-6.98 (m, 2H), 7.40-7.42 (m, 2H).

EXAMPLE 754-[(8-cyclohexyl-2,8-diazaspiro[4.5]dec-2-yl)methyl]-N-[2-(1H-imidazol-2-yl)-1-(1H-imidazol-2-ylmethyl)ethyl]cyclohexanamine

A 4N dioxane solution (2 mL) of the compound (50 mg) produced in Example74 was stirred at 50° C. for 2 hours. The reaction solution wasconcentrated under reduced pressure. The residue was purified by silicagel chromatography (ethyl acetate:methanol: 28% aqueousammonia=90:10:0→80:20:2→dichloromethane:methanol: 28% aqueousammonia=80:20:2→80:20:4) to obtain the title compound (23 mg) having thefollowing physical properties.

TLC: Rf 0.21 (dichloromethane:methanol:28% aqueous ammonia=8:2:0.2);

NMR (CDCl₃): δ 0.82-3.00 (m, 41H), 3.32 (m, 1H), 6.92-7.08 (m, 4H).

EXAMPLE 762,2′-{2-[{4-[(8-cyclohexyl-2,8-diazaspiro[4.5]dec-2-yl)methyl]cyclohexyl}(methyl)amino]-1,3-propanyl}bis(N,N-dimethyl-1H-imidazole-1-sulfonamide)

Except for using the compound (47 mg) produced in Example 74 in place ofthe compound produced in Example 20, the same operation as in Example 22was performed to obtain the title compound (42 mg) having the followingphysical properties.

TLC: Rf 0.54 (ethyl acetate:methanol:28% aqueous ammonia=8:2:0.4);

NMR (CDCl₃): δ 0.76-2.70 (m, 40H), 2.80-2.95 (m, 12H), 2.95-3.10 (m,2H), 3.20-3.25 (m, 2H), 4.14 (m, 1H), 6.90-6.95 (m, 2H), 7.14-7.20 (m,2H).

EXAMPLE 774-[(8-cyclohexyl-2,8-diazaspiro[4.5]dec-2-yl)methyl]-N-[2-(1H-imidazol-2-yl)-1-(1H-imidazol-2-ylmethyl)ethyl]-N-methylcyclohexanamine

To a methanol (3 mL) solution of the compound (42 mg) produced inExample 76, a 4N dioxane solution (3 mL) was added, followed by stirringat 50° C. for 2 hour. The reaction solution was concentrated underreduced pressure. The residue was purified by silica gel chromatography(dichloromethane:methanol: 28% aqueous ammonia=100:10:0→80:20:3) toobtain the title compound (16 mg) having the following physicalproperties.

TLC: Rf 0.32 (dichloromethane:methanol:28% aqueous ammonia=8:2:0.4);

NMR (CDCl₃): δ 0.80-2.60 (m, 40H), 2.60-2.78 (m, 2H), 2.80-2.92 (m, 2H),3.45 (m, 1H), 6.95 (m, 4H).

EXAMPLE 784-formyl-N-{3-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl)-2-[(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl)methyl]propyl}benzamide

To a dimethylformamide (2 mL) solution of the compound (300 mg) producedin Example 29 and 4-formylbenzoic acid (116 mg),1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide (hereafter abbreviatedto EDC) (274 mg) and 1-hydroxybenzimidazole (104 mg) were added in thisorder. The reaction solution was stirred at room temperature for 17hour. To the reaction solution, water (10 mL) was added. The aqueouslayer was extracted twice with dichloromethane (20 mL). The combinedorganic layer was washed with saturated sodium chloride solution (20 mL)and then dried over anhydrous magnesium sulfate. After removing theanhydrous magnesium sulfate by filtration, the filtrate wasconcentrated. The residue was purified by silica gel chromatography(ethyl acetate:methanol: 28% aqueous ammonia=1:0:0→100:10:1) to obtainthe title compound (510 mg).

TLC: Rf 0.76 (ethyl acetate:methanol:28% aqueous ammonia=8:2:0.2);

NMR (CDCl₃): δ-0.03 (s, 18H), 0.86 (t, J=8.4 Hz, 4H), 2.78-3.02 (m, 5H),3.44 (t, J=8.4 Hz, 4H), 3.60 (t, J=5.1 Hz, 2H), 5.18 (s, 4H), 6.92 (d,J=1.2 Hz, 2H), 6.95 (d, J=1.2 Hz, 2H), 7.94 (d, J=8.4 Hz, 2H), 8.10 (d,J=8.4 Hz, 2H), 9.47 (m, 1H), 10.08 (s, 1H).

EXAMPLE 794-[(8-isobutyl-2,8-diazaspiro[4.5]dec-2-yl)methyl]-N-{3-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl)-2-[(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl)methyl]propyl}benzamide

Except for using the compound (60 mg) produced in Example 78 in place of4-(diethoxymethyl)benzaldehyde, the same operation as in Example 26 wasperformed to obtain the title compound (82 mg) having the followingphysical properties.

TLC: Rf 0.62 (ethyl acetate:methanol:28% aqueous ammonia=9:1:0.2);

NMR (CDCl₃): δ-0.03 (s, 18H), 0.80-1.02 (m, 10H), 1.40-3.80 (m, 30H),5.20 (s, 4H), 6.93 (d, J=2.1 Hz, 2H), 6.96 (d, J=2.1 Hz, 2H), 7.37 (d,J=8.1 Hz, 2H), 8.84 (d, J=8.1 Hz, 2H), 8.71 (m, 1H).

EXAMPLE 80N-[3-(1H-imidazol-2-yl)-2-(1H-imidazol-2-ylmethyl)propyl]-4-[(8-isobutyl-2,8-diazaspiro[4.5]dec-2-yl)methyl]benzamide

Except for using the compound (82 mg) produced in Example 79 in place ofthe compound produced in Example 20, the same operation as in Example 21was performed to obtain the title compound (65 mg) having the followingphysical properties.

TLC: Rf 0.29 (ethyl acetate:methanol:28% aqueous ammonia=8:2:0.4);

NMR (CD₃OD): δ 1.03 (d, J=6.6 Hz, 6H), 1.88-2.24 (m, 7H), 2.77 (m, 1H),2.92-3.66 (m, 16H), 4.46 (s, 2H), 7.42 (s, 4H), 7.64 (d, J=8.1 Hz, 2H),7.94 (d, J=8.1 Hz, 2H).

EXAMPLE 80(1)-EXAMPLE 80(4)

Except for using the corresponding amine in place of8-isobutyl-2,8-diazaspiro[4.5]decane in Example 79, the same operationas in Example 79→Example 80 was performed to obtain the followingcompounds.

EXAMPLE 80(1)4-[(8-cyclohexyl-2,8-diazaspiro[4.5]dec-2-yl)methyl]-N-[3-(1H-imidazol-2-yl)-2-(1H-imidazol-2-ylmethyl)propyl]benzamide

TLC: Rf 0.59 (ethyl acetate:methanol:28% aqueous ammonia=8:2:0.4);

NMR (CDCl₃): δ 1.00-1.92 (m, 16H), 2.18-2.65 (m, 8H), 2.34 (s, 2H), 2.56(t, J=6.9 Hz, 2H), 2.78 (dd, J=14.4, 5.4 Hz, 2H), 3.45 (t, J=6.9 Hz,2H), 3.62 (s, 2H), 6.90-7.10 (m, 4H), 7.41 (d, J=8.1 Hz, 2H), 7.84 (d,J=8.1 Hz, 2H), 8.26 (m, 1H).

EXAMPLE 80(2)4-({[4-(dipropylamino)butyl]amino}methyl)-N-[3-(1H-imidazol-2-yl)-2-(1H-imidazol-2-ylmethyl)propyl]benzamide

TLC: Rf 0.29 (ethyl acetate:methanol:28% aqueous ammonia=8:2:0.4);

NMR (CD₃OD): δ 1.01 (t, J=7.2 Hz, 6H), 1.64-1.90 (m, 8H), 2.65 (m, 1H),2.82-3.20 (m, 12H), 3.40 (d, J=6.0 Hz, 2H), 4.27 (s, 2H), 7.25 (s, 4H),7.61 (d, J=8.4 Hz, 2H), 7.94 (d, J=8.4 Hz, 2H).

EXAMPLE 80(3) Ethyl2-(4-{[3-(1H-imidazol-2-yl)-2-(1H-imidazol-2-ylmethyl)propyl]carbamoyl}benzyl)-8-isobutyl-2,8-diazaspiro[4.5]decane-3-carboxylate

TLC: Rf 0.69 (ethyl acetate:methanol:28% aqueous ammonia=8:2:0.4);

NMR (CDCl₃): δ 0.85 (d, J=6.3 Hz, 6H), 1.25 (t, J=7.2 Hz, 3H), 1.40-2.40(m, 15H), 2.59 (dd, J=14.4, 6.9 Hz, 2H), 2.78 (dd, J=14.4, 5.1 Hz, 2H),2.86 (d, J=9.3 Hz, 1H), 3.36 (t, J=8.1 Hz, 1H), 3.45 (t, J=5.4 Hz, 2H),3.51 (d, J=13.8 Hz, 1H), 4.02 (d, J=13.8 Hz, 1H), 4.10-4.22 (m, 2H),7.00 (s, 4H), 7.43 (d, J=8.4 Hz, 2H), 7.85 (d, J=8.4 Hz, 2H), 8.47 (m,1H).

EXAMPLE 80(4)4-({[4-(1-azepanyl)cyclohexyl]amino}methyl)-N-[3-(1H-imidazol-2-yl)-2-(1H-imidazol-2-ylmethyl)propyl]benzamide

TLC: Rf 0.25, 0.15 (ethyl acetate:methanol:28% aqueous ammonia=8:2:0.4);

NMR (CD₃OD): δ 1.22-2.26 (m, 16H), 2.42-3.40 (m, 13H), 3.89 (s, 2H),6.96 (s, 4H), 7.42-7.58 (m, 2H), 7.80-7.94 (m, 2H).

EXAMPLE 812-(4-{[3-(1H-imidazol-2-yl)-2-(1H-imidazol-2-ylmethyl)propyl]carbamoyl}benzyl)-8-isobutyl-2,8-diazaspiro[4.5]decane-3-carboxylicAcid

To a tetrahydrofuran (2 mL)-methanol (2 mL) solution of the compound (51mg) produced in Example 80(3), an aqueous 2N sodium hydroxide solution(0.5 mL) was added. The reaction solution was stirred at 50° C. for 3hours. To the reaction solution, 1N hydrochloric acid was added so as toadjust the pH to about 5. The reaction solution was concentrated underreduced pressure. The residue was washed with ethanol. An insoluble saltwas removed by filtration, and then the filtrate was concentrated. Theresidue was purified by silica gel chromatography(dichloromethane:methanol: 28% aqueous ammonia=8:2:0.5) to obtain thetitle compound (35 mg) having the following physical properties.

TLC: Rf 0.35 (dichloromethane:methanol:28% aqueous ammonia=8:2:0.5);

NMR (CD₃OD): δ 0.95 (d, J=6.6 Hz, 6H), 1.65-2.20 (m, 7H), 2.40-2.95 (m,12H), 3.08 (d, J=12.0 Hz, 1H), 3.20-3.38 (m, 2H), 3.49 (m, 1H), 3.78 (d,J=12.6 Hz, 1H), 4.29 (d, J=12.6 Hz, 1H), 6.97 (s, 4H), 7.56 (d, J=8.4Hz, 2H), 7.83 (d, J=8.4 Hz, 2H).

EXAMPLE 82N-[2-(4-morpholinyl)ethyl]-3-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl)-2-[(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl)methyl]-1-propanamine

Except for using the compound (200 mg) produced in Example 19 in placeof 4-(diethoxymethyl)benzaldehyde and using 2-morpholin-4-ylethaneamine(112 mg) in place of 8-isobutyl-2,8-diazaspiro[4.5]decane, the sameoperation as in Example 26 was performed to obtain the title compound(184 mg) having the following physical properties.

TLC: Rf 0.42 (ethyl acetate:methanol:28% aqueous ammonia=8:2:0.2);

NMR (CDCl₃): δ-0.03 (s, 18H), 0.88 (t, J=8.4 Hz, 4H), 2.30-2.95 (m,15H), 3.45 (t, J=8.4 Hz, 4H), 3.62-3.78 (m, 4H), 5.20 (d, J=10.8 Hz,2H), 5.28 (d, J=10.8 Hz, 2H), 6.88 (d, J=1.2 Hz, 2H), 6.91 (d, J=1.2 Hz,2H).

EXAMPLE 834-formyl-N-[2-(4-morpholinyl)ethyl]-N-{3-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl)-2-[(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl)methyl]propyl}benzamide

Except for using the compound (184 mg) produced in Example 82 and4-formylbenzoic acid (63 mg), the same operation as in Example 78 wasperformed to obtain the title compound (88 mg) having the followingphysical properties.

TLC: Rf 0.47 (ethyl acetate:methanol:28% aqueous ammonia=8:2:0.2);

NMR (CDCl₃): δ-0.03 (s, 18H), 0.88 (t, J=7.5 Hz, 4H), 2.10-3.86 (m,23H), 5.00-5.35 (m, 4H), 6.75-7.00 (m, 4H), 7.48 (d, J=8.1 Hz, 2H), 7.88(d, J=8.1 Hz, 2H), 10.03 (s, 1H).

EXAMPLE 844-[(8-isobutyl-2,8-diazaspiro[4.5]dec-2-yl)methyl]-N-[2-(4-morpholinyl)ethyl]-N-{3-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl)-2-[(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl)methyl]propyl}benzamide

Except for using the compound (88 mg) produced in Example 83 in place of4-(diethoxymethyl)benzaldehyde and using8-isobutyl-2,8-diazaspiro[4.5]decane (38 mg) in place of8-isobutyl-2,8-diazaspiro[4.5]decane, the same operation as in Example26 was performed to obtain the title compound (122 mg) having thefollowing physical properties.

TLC: Rf 0.33 (ethyl acetate:methanol:28% aqueous ammonia=9:1:0.1);

NMR (CDCl₃): δ-0.03 (s, 18H), 0.80-0.98 (m, 10H), 1.20-3.86 (m, 42H),5.00-5.38 (m, 4H), 6.78-7.00 (m, 4H), 7.08-7.41 (m, 4H).

EXAMPLE 85N-[3-(1H-imidazol-2-yl)-2-(1H-imidazol-2-ylmethyl)propyl]-4-[(8-isobutyl-2,8-diazaspiro[4.5]dec-2-yl)methyl]-N-[2-(4-morpholinyl)ethyl]benzamide

Except for using the compound (122 mg) produced in Example 84 in placeof the compound produced in Example 20, the same operation as in Example21 was performed to obtain the title compound (49 mg) having thefollowing physical properties.

TLC: Rf 0.63 (ethyl acetate:methanol:28% aqueous ammonia=8:2:0.4);

NMR (CDCl₃): δ 0.87 (d, J=6.6 Hz, 6H), 1.45-1.86 (m, 7H), 2.02 (d, J=7.2Hz, 2H), 2.15-2.52 (m, 15H), 2.54 (t, J=7.2 Hz, 2H), 2.80 (dd, J=13.5,3.3 Hz, 2H), 3.40-3.72 (m, 10H), 7.03 (s, 4H), 7.35 (d, J=8.1 Hz, 2H),7.41 (d, J=8.1 Hz, 2H).

EXAMPLE 85(1)-EXAMPLE 85(9)

Except for using the corresponding amine in place of2-morpholin-4-ylethaneamine in Example 82, the same operation as inExample 82→Example 83→Example 84→Example 85 was sequentially performedto obtain the following compounds.

EXAMPLE 85(1)N-(2-acetamidoethyl)-N-[3-(1H-imidazol-2-yl)-2-(1H-imidazol-2-ylmethyl)propyl]-4-[(8-isobutyl-2,8-diazaspiro[4.5]dec-2-yl)methyl]benzamide

TLC: Rf 0.60 (ethyl acetate:methanol:28% aqueous ammonia=8:2:0.4);

NMR (CDCl₃): δ 0.87 (d, J=6.6 Hz, 6H), 1.48-1.68 (m, 6H), 1.76 (m, 1H),1.85-2.62 (m, 16H), 2.75-2.88 (m, 2H), 3.30-3.90 (m, 8H), 5.85 (m, 1H),6.80-7.20 (m, 4H), 7.33 (d, J=7.5 Hz, 2H), 7.41 (d, J=7.5 Hz, 2H).

EXAMPLE 85(2)N-(2-aminoethyl)-N-[3-(1H-imidazol-2-yl)-2-(1H-imidazol-2-ylmethyl)propyl]-4-[(8-isobutyl-2,8-diazaspiro[4.5]dec-2-yl)methyl]benzamide

TLC: Rf 0.29 (ethyl acetate:methanol:28% aqueous ammonia=8:2:0.4);

NMR (CDCl₃): δ 0.87 (d, J=6.6 Hz, 6H), 1.45-1.90 (m, 7H), 2.02 (d, J=7.2Hz, 2H), 2.20-2.90 (m, 15H), 3.43 (t, J=7.2 Hz, 2H), 3.50-3.72 (m, 4H),7.03 (s, 4H), 7.34 (d, J=8.1 Hz, 2H), 7.40 (d, J=8.1 Hz, 2H).

EXAMPLE 85(3)N-(3-aminopropyl)-N-[3-(1H-imidazol-2-yl)-2-(1H-imidazol-2-ylmethyl)propyl]-4-[(8-isobutyl-2,8-diazaspiro[4.5]dec-2-yl)methyl]benzamide

TLC: Rf 0.19 (ethyl acetate:methanol:28% aqueous ammonia=8:2:0.4);

NMR (CDCl₃): δ 0.87 (d, J=6.6 Hz, 6H), 1.45-1.88 (m, 9H), 1.98-2.62 (m,15H), 2.72-2.90 (m, 2H), 3.43 (t, J=7.8 Hz, 2H), 3.50-3.66 (m, 2H), 3.61(s, 2H), 7.03 (s, 4H), 7.33 (d, J=8.1 Hz, 2H), 7.41 (d, J=8.1 Hz, 2H).

EXAMPLE 85(4)N-(4-aminobutyl)-N-[3-(1H-imidazol-2-yl)-2-(1H-imidazol-2-ylmethyl)propyl]-4-[(8-isobutyl-2,8-diazaspiro[4.5]dec-2-yl)methyl]benzamide

TLC: Rf 0.48 (dichloromethane:methanol:28% aqueous ammonia=8:2:0.4);

NMR (CDCl₃): δ 0.87 (d, J=6.6 Hz, 6H), 1.20-1.94 (m, 11H), 2.03 (d,J=7.5 Hz, 2H), 2.20-2.62 (m, 13H), 2.75-2.90 (m, 2H), 3.34 (t, J=7.2 Hz,2H), 3.48-3.66 (m, 2H), 3.61 (s, 2H), 7.03 (s, 4H), 7.32 (d, J=8.1 Hz,2H), 7.41 (d, J=8.1 Hz, 2H).

EXAMPLE 85(5)N-(5-aminopentyl)-N-[3-(1H-imidazol-2-yl)-2-(1H-imidazol-2-ylmethyl)propyl]-4-[(8-isobutyl-2,8-diazaspiro[4.5]dec-2-yl)methyl]benzamide

TLC: Rf 0.47 (dichloromethane:methanol:28% aqueous ammonia=8:2:0.4);

NMR (CDCl₃): δ 0.87 (d, J=6.6 Hz, 6H), 1.06-1.72 (m, 12H), 1.77 (m, 1H),1.98-2.68 (m, 15H), 2.75-2.90 (m, 2H), 3.32 (t, J=7.8 Hz, 2H), 3.46-3.66(m, 2H), 3.61 (s, 2H), 7.03 (s, 4H), 7.31 (d, J=8.1 Hz, 2H), 7.41 (d,J=8.1 Hz, 2H).

EXAMPLE 85(6)N-(6-aminohexyl)-N-[3-(1H-imidazol-2-yl)-2-(1H-imidazol-2-ylmethyl)propyl]-4-[(8-isobutyl-2,8-diazaspiro[4.5]dec-2-yl)methyl]benzamide

TLC: Rf 0.15 (ethyl acetate:methanol:28% aqueous ammonia=8:2:0.4);

NMR (CDCl₃): δ 0.87 (d, J=6.6 Hz, 6H), 1.05-1.84 (m, 15H), 2.02 (d,J=7.5 Hz, 2H), 2.15-2.66 (m, 13H), 2.80 (dd, J=13.5, 3.6 Hz, 2H), 3.30(t, J=7.8 Hz, 2H), 3.46-3.62 (m, 2H), 3.61 (s, 2H), 7.04 (s, 4H), 7.31(d, J=8.1 Hz, 2H), 7.41 (d, J=8.1 Hz, 2H).

EXAMPLE 85(7)N-[2-(dimethylamino)ethyl]-N-[3-(1H-imidazol-2-yl)-2-(1H-imidazol-2-ylmethyl)propyl]-4-[(8-isobutyl-2,8-diazaspiro[4.5]dec-2-yl)methyl]benzamide

TLC: Rf 0.66 (ethyl acetate:methanol:28% aqueous ammonia=8:2:0.4);

NMR (CDCl₃): δ 0.87 (d, J=6.6 Hz, 6H), 1.42-1.82 (m, 7H), 1.98-2.05 (m,2H), 2.03 (s, 6H), 2.16-2.52 (m, 11H), 2.55 (t, J=6.6 Hz, 2H), 2.81 (dd,J=13.5, 3.3 Hz, 2H), 3.43 (t, J=6.9 Hz, 2H), 3.50-3.62 (m, 2H), 3.60 (s,2H), 7.03 (s, 4H), 7.33 (d, J=8.1 Hz, 2H), 7.40 (d, J=8.1 Hz, 2H).

EXAMPLE 85(8)N-[3-(1H-imidazol-2-yl)-2-(1H-imidazol-2-ylmethyl)propyl]-4-[(8-isobutyl-2,8-diazaspiro[4.5]dec-2-yl)methyl]-N-(2-methoxyethyl)benzamide

TLC: Rf 0.56 (ethyl acetate:methanol:28% aqueous ammonia=8:2:0.4);

NMR (DMSO-d₆): δ 0.93 (d, J=6.6 Hz, 6H), 1.68-2.12 (m, 7H), 2.30-4.20(m, 26H), 7.18-7.60 (m, 8H).

EXAMPLE 85(9)N-[3-(1H-imidazol-2-yl)-2-(1H-imidazol-2-ylmethyl)propyl]-4-[(8-isobutyl-2,8-diazaspiro[4.5]dec-2-yl)methyl]-N-[2-(1-pyrrolidinyl)ethyl]benzamide

TLC: Rf 0.34 (ethyl acetate:methanol:28% aqueous ammonia=8:2:0.4);

NMR (DMSO-d₆): δ 0.83 (d, J=6.6 Hz, 6H), 1.42-1.88 (m, 11H), 1.98-2.80(m, 21H), 3.10-3.60 (m, 4H), 3.58 (s, 2H), 6.78-7.00 (m, 4H), 7.18-7.38(m, 4H).

EXAMPLE 86 4-[(8-cyclohexyl-2,8-diazaspiro[4.5]dec-2-yl)methyl]benzoicAcid

Except for using 4-formylbenzoic acid (112 mg) in place of4-(diethoxymethyl)benzaldehyde and using8-cyclohexyl-2,8-diazaspiro[4.5]decane (170 mg) in place of8-isobutyl-2,8-diazaspiro[4.5]decane, the same operation as in Example26 was performed to obtain the title compound (450 mg) having thefollowing physical properties.

TLC: Rf 0.28 (dichloromethane:methanol:28% aqueous ammonia=8:2:0.2);

NMR (CD₃OD): δ 1.05-2.18 (m, 16H), 2.57 (s, 2H), 2.75 (t, J=6.9 Hz, 2H),3.00-3.25 (m, 5H), 3.74 (s, 2H), 7.37 (d, J=8.1 Hz, 2H), 7.95 (d, J=8.1Hz, 2H).

EXAMPLE 874-[(8-cyclohexyl-2,8-diazaspiro[4.5]dec-2-yl)methyl]-N-{3-hydroxy-2,2-bis[(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl)methyl]propyl}benzamide

Except for using the compound (137 mg) produced in Example 86 in placeof 4-formylbenzoic acid and using the compound (73 mg) produced inExample 34 in place of the compound produced in Example 29, the sameoperation as in Example 78 was performed to obtain the title compound(100 mg) having the following physical properties.

TLC: Rf 0.74 (ethyl acetate:methanol:28% aqueous ammonia=8:2:0.4);

NMR (CDCl₃): δ-0.03 (s, 18H), 0.80-1.98 (m, 20H), 2.00-3.60 (m, 21H),3.62 (s, 2H), 5.15-5.38 (m, 4H), 6.82-7.02 (m, 4H), 7.41 (d, J=8.4 Hz,2H), 7.92 (d, J=8.4 Hz, 2H), 9.40 (m, 1H).

EXAMPLE 883-({4-[(8-cyclohexyl-2,8-diazaspiro[4.5]dec-2-yl)methyl]benzoyl}amino)-2,2-bis[(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl)methyl]propylAcetate

Except for using the compound (100 mg) produced in Example 87 in placeof the compound produced in Example 35, the same operation as in Example36 was performed to obtain the title compound (10 mg) having thefollowing physical properties.

TLC: Rf 0.52 (ethyl acetate:methanol:28% aqueous ammonia=9:1:0.2);

NMR (CDCl₃): δ-0.03 (s, 18H), 0.87 (t, J=8.4 Hz, 4H), 1.00-1.98 (m,16H), 2.05 (s, 3H), 2.10-2.62 (m, 9H), 2.95 (d, J=15.9 Hz, 2H), 3.16 (d,J=15.9 Hz, 2H), 3.45 (t, J=8.4 Hz, 4H), 3.50 (s, 2H), 3.63 (s, 2H), 4.09(s, 2H), 5.14 (d, J=11.1 Hz, 2H), 5.36 (d, J=11.1 Hz, 2H), 6.90 (d,J=1.5 Hz, 2H), 6.97 (d, J=1.5 Hz, 2H), 7.39 (d, J=8.1 Hz, 2H), 7.92 (d,J=8.1 Hz, 2H), 9.78 (m, 1H).

EXAMPLE 893-({4-[(8-cyclohexyl-2,8-diazaspiro[4.5]dec-2-yl)methyl]benzoyl}amino)-2,2-bis(1H-imidazol-2-ylmethyl)propylAcetate

Except for using the compound (10 mg) produced in Example 88 in place ofthe compound produced in Example 20, the same operation as in Example 21was performed to obtain the title compound (8 mg) having the followingphysical properties.

TLC: Rf 0.35 (ethyl acetate:methanol:28% aqueous ammonia=8:2:0.4);

NMR (CD₃OD): δ 1.10-2.25 (m, 16H), 1.95 (s, 3H), 2.98-3.64 (m, 15H),3.97 (s, 2H), 4.45-4.52 (m, 2H), 7.45 (s, 4H), 7.64-7.72 (m, 2H), 8.03(d, J=8.4 Hz, 2H).

EXAMPLE 90 Tert-butyl 4-[(benzoyloxy)methyl]-1-piperidinecarboxylate

To a dichloromethane (30 mL) solution of N-boc-4-piperidine methanol(2.29 g), triethylamine (4.45 mL) was added. After cooling to 0° C.,benzoylchloride (2.49 mL) was added. The reaction solution was stirredfor 2 hours with heating to room temperature. To the reaction solution,water (50 mL) was added. The aqueous layer was extracted twice withethyl acetate (50 mL). The combined organic layer was washed withsaturated sodium chloride solution (50 mL) and then dried over anhydrousmagnesium sulfate. After removing the anhydrous magnesium sulfate byfiltration, the filtrate was concentrated. The residue was purified bysilica gel chromatography (n-hexane:ethyl acetate=100:0→10:1→ethylacetate:methanol=90:10) to obtain (2.30 g) having the following physicalproperties.

TLC: Rf 0.41 (n-hexane:ethyl acetate=1:1);

NMR (CDCl₃): δ 1.20-1.88 (m, 13H), 1.97 (m, 1H), 2.60-2.85 (m, 2H),4.00-4.30 (m, 4H), 7.40-7.65 (m, 3H), 8.00-8.15 (m, 2H).

EXAMPLE 91 4-piperidinylmethyl Benzoate

To a methanol (30 mL) solution of the compound (1.91 g) produced inExample 90, a 4N dioxane solution (10 mL) was added, followed bystirring at room temperature for 3 hours. The reaction solution wasconcentrated under reduced pressure. Without purifying the residue, thetitle compound (1.44 g) having the following physical properties wasobtained.

TLC: Rf 0.56 (dichloromethane:methanol:28% aqueous ammonia=8:2:0.5);

NMR (DMSO-d₆): δ 1.42-1.62 (m, 2H), 1.82-1.95 (m, 2H), 2.05 (m, 1H),2.80-2.98 (m, 2H), 3.20-3.40 (m, 2H), 4.18 (d, J=6.0 Hz, 2H), 7.50-7.60(m, 2H), 7.64-7.72 (m, 1H), 7.98-8.04 (m, 2H), 8.40-8.95 (m, 2H).

EXAMPLE 92{1-[3-{1-[(dimethylamino)sulfonyl]-1H-imidazol-2-yl}-2-({1-[(dimethylamino)sulfonyl]-1H-imidazol-2-yl}methyl)propanoyl]-4-piperidinyl}methylBenzoate

To a dichloromethane (5 mL) solution of the compound (327 mg) producedin Example 91 and the compound (370 mg) produced in Example 68,N-methylmorpholine (280 μL), EDC (452 mg) and 1-hydroxybenzimidazole(138 mg) were added in this order. The reaction solution was stirred atroom temperature overnight. To the reaction solution, water (10 mL) wasadded. The aqueous layer was extracted twice with dichloromethane (20mL). The combined organic layer was washed with saturated sodiumchloride solution (20 mL) and then dried over anhydrous magnesiumsulfate. After removing the anhydrous magnesium sulfate by filtration,the filtrate was concentrated. The residue was purified by silica gelchromatography (n-hexane:ethyl acetate=1:1→0:1→ethylacetate:methanol:28% aqueous ammonia=90:10:0→90:10:1) to obtain thetitle compound (400 mg) having the following physical properties.

TLC: Rf 0.54 (ethyl acetate:methanol:28% aqueous ammonia=9:1:0.2);

NMR (CDCl₃): δ 1.12-1.50 (m, 2H), 1.72-1.92 (m, 2H), 2.02 (m, 1H), 2.66(m, 1H), 2.88 (s, 12H), 2.95-3.44 (m, 5H), 4.15-4.32 (m, 4H), 4.62 (m,1H), 6.85 (d, J=1.8 Hz, 1H), 6.90 (d, J=1.8 Hz, 1H), 7.17 (d, J=1.8 Hz,1H), 7.20 (d, J=1.8 Hz, 1H), 7.42-7.48 (m, 2H), 7.58-7.60 (m, 1H),8.00-8.08 (m, 2H).

EXAMPLE 932,2′-(2-{[4-(hydroxymethyl)-1-piperidinyl]carbonyl}-1,3-propanyl)bis(N,N-dimethyl-1H-imidazole-1-sulfonamide)

To a tetrahydrofuran (2 mL)-methanol (2 mL) solution of the compound(400 mg) produced in Example 92, an aqueous 2N sodium hydroxide solution(3 mL) was added. The reaction solution was stirred at 50° C. for onehour. The reaction solution was concentrated under reduced pressure. Tothe residue, water (20 mL) was added. The aqueous layer was extractedtwice with dichloromethane (50 mL). The combined organic layer waswashed in turn with an aqueous 5N sodium hydroxide solution (50 mL) andsaturated sodium chloride solution (50 mL), and then dried overanhydrous magnesium sulfate. After removing the anhydrous magnesiumsulfate by filtration, the filtrate was concentrated. Without purifyingthe residue, the title compound (260 mg) was obtained.

TLC: Rf 0.49 (ethyl acetate:methanol:28% aqueous ammonia=8:2:0.2);

NMR (CDCl₃): δ 1.00-1.85 (m, 5H), 2.53 (m, 1H), 2.90 (s, 12H), 2.92-3.42(m, 5H), 3.48 (d, J=6.0 Hz, 2H), 4.15-4.30 (m, 2H), 4.58 (m, 1H), 6.86(d, J=1.5 Hz, 1H), 6.88 (d, J=1.5 Hz, 1H), 7.15-7.20 (m, 2H).

EXAMPLE 942,2′-{2-[(4-formyl-1-piperidinyl)carbonyl]-1,3-propanyl}bis(N,N-dimethyl-1H-imidazole-1-sulfonamide)

Except for using the compound (130 mg) produced in Example 93 in placeof the compound produced in Example 9, the same operation as in Example10 was performed to obtain the title compound (128 mg) having thefollowing physical properties.

TLC: Rf 0.39 (ethyl acetate:methanol:28% aqueous ammonia=9:1:0.2);

NMR (CDCl₃): δ 0.92-2.02 (m, 4H), 2.40-3.45 (m, 6H), 2.92 (s, 12H),4.04-4.72 (m, 4H), 6.82-6.92 (m, 2H), 7.22 (s, 2H), 9.66 (s, 1H).

EXAMPLE 952,2′-(2-{[4-({8-[(3-methyl-2-thienyl)methyl]-2,8-diazaspiro[4.5]dec-2-yl}methyl)-1-piperidinyl]carbonyl}-1,3-propanyl)bis(N,N-dimethyl-1H-imidazole-1-sulfonamide)

Except for using the compound (128 mg) produced in Example 94 in placeof 4-(diethoxymethyl)benzaldehyde and using the compound (61 mg)produced in Example 13 in place of 8-isobutyl-2,8-diazaspiro[4.5]decane,the same operation as in Example 26 was performed to obtain the titlecompound (42 mg) having the following physical properties.

TLC: Rf 0.56 (ethyl acetate:methanol:28% aqueous ammonia=8:2:0.2);

NMR (CDCl₃): δ 0.90-3.42 (m, 27H), 2.19 (s, 3H), 2.90 (s, 12H), 3.60 (s,2H), 4.10-4.28 (m, 2H), 4.52 (m, 1H), 6.77 (d, J=5.1 Hz, 1H), 6.86 (d,J=1.8 Hz, 1H), 6.87 (d, J=1.8 Hz, 1H), 7.11 (d, J=5.1 Hz, 1H), 7.17 (d,J=1.8 Hz, 2H).

EXAMPLE 962-({1-[3-(1H-imidazol-2-yl)-2-(1H-imidazol-2-ylmethyl)propanoyl]-4-piperidinyl}methyl)-8-[(3-methyl-2-thienyl)methyl]-2,8-diazaspiro[4.5]decane

To the compound (78 mg) produced in Example 95, 2N hydrochloric acid (3mL) was added, followed by stirring at 70° C. for 6 hours. The reactionsolution was concentrated under reduced pressure. The residue waspurified by silica gel chromatography (ethyl acetate:methanol: 28%aqueous ammonia=8:2:0.2) to obtain the title compound (32 mg) having thefollowing physical properties.

TLC: Rf 0.22 (ethyl acetate:methanol:28% aqueous ammonia=8:2:0.2);

NMR (CDCl₃): δ 1.02-1.22 (m, 2H), 1.58-2.00 (m, 9H), 2.19 (s, 3H),2.35-3.20 (m, 16H), 3.65 (s, 2H), 3.73 (m, 1H), 4.21 (m, 1H), 4.51 (m,1H), 6.78 (d, J=5.4 Hz, 1H), 7.03 (s, 4H), 7.13 (d, J=5.4 Hz, 1H).

EXAMPLE 96(1)N′-({1-[3-(1H-imidazol-2-yl)-2-(1H-imidazol-2-ylmethyl)propanoyl]-4-piperidinyl}methyl)-N,N-dipropyl-1,4-butanediamine

Except for using the corresponding amine in place of the compoundproduced in Example 13 in Example 95, the same operation as in Example95→Example 96 was sequentially performed to obtain the title compoundhaving the following physical properties.

TLC: Rf 0.34 (dichloromethane:methanol:28% aqueous ammonia=8:2:0.2);

NMR (CDCl₃): δ 0.89 (t, J=7.2 Hz, 6H), 1.08-1.96 (m, 13H), 2.40-2.85 (m,13H), 2.90-3.05 (m, 2H), 3.14 (m, 1H), 3.27 (m, 1H), 4.14 (m, 1H), 4.63(m, 1H), 7.01 (s, 4H).

EXAMPLE 972-({1-[3-(1H-imidazol-2-yl)-2-(1H-imidazol-2-ylmethyl)propyl]-4-piperidinyl}methyl)-8-[(3-methyl-2-thienyl)methyl]-2,8-diazaspiro[4.5]decane

Except for using the compound (170 mg) produced in Example 92 in placeof the compound produced in Example 5 in Example 18, the same operationas in Example 18→Example 94→Example 95→Example 96 was sequentiallyperformed to obtain the title compound having the following physicalproperties.

TLC: Rf 0.54 (dichloromethane:methanol:28% aqueous ammonia=9:1:0.2);

NMR (CDCl₃): δ 1.18-2.72 (m, 33H), 2.80-2.98 (m, 2H), 3.59 (s, 2H), 6.78(d, J=5.4 Hz, 1H), 6.90-7.02 (m, 4H), 7.12 (d, J=5.4 Hz, 1H).

EXAMPLE 98N-{4-[(8-cyclohexyl-2,8-diazaspiro[4.5]dec-2-yl)methyl]benzyl}-3-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl)-2-[(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl)methyl]propanamide

Except for using the compound (50 mg) produced in Example 5 and1-{4-[(8-cyclohexyl-2,8-diazaspiro[4.5]dec-2-yl)methyl]phenyl}methaneamine(37 mg), the same operation as in Example 78 was performed to obtain thetitle compound (65 mg) having the following physical properties.

TLC: Rf 0.47 (ethyl acetate:methanol:28% aqueous ammonia=8:2:0.2);

NMR (CDCl₃): δ-0.03 (s, 18H), 0.80-0.92 (m, 4H), 1.00-1.90 (m, 16H),1.95-2.60 (m, 9H), 2.98-3.68 (m, 11H), 4.28 (d, J=5.7 Hz, 2H), 5.10 (d,J=10.8 Hz, 2H), 5.26 (d=10.8 Hz, 2H), 6.82-6.90 (m, 4H), 6.97 (d, J=8.1Hz, 2H), 7.17 (d, J=8.1 Hz, 2H), 7.60 (m, 1H).

EXAMPLE 99N-{4-[(8-cyclohexyl-2,8-diazaspiro[4.5]dec-2-yl)methyl]benzyl}-3-(1H-imidazol-2-yl)-2-(1H-imidazol-2-ylmethyl)propanamide

Except for using the compound (65 mg) produced in Example 98 in place ofthe compound produced in Example 20, the same operation as in Example 21was performed to obtain the title compound (8 mg) having the followingphysical properties.

TLC: Rf 0.18 (ethyl acetate:methanol:28% aqueous ammonia=8:2:0.4);

NMR (CDCl₃): δ 1.00-1.92 (m, 16H), 2.12-2.60 (m, 9H), 2.75-3.02 (m, 5H),3.55 (brs, 2H), 4.41 (brs, 2H), 6.98 (s, 4H), 7.15 (d, J=8.4 Hz, 2H),7.24-7.28 (m, 2H).

EXAMPLE 99(1)-EXAMPLE 99(4)

Except for using the corresponding amine in place of1-{4-[(8-cyclohexyl-2,8-diazaspiro[4.5]dec-2-yl)methyl]phenyl}methaneaminein Example 98, the same operation as in Example 98→Example 99 wassequentially performed to obtain the following compounds.

EXAMPLE 99(1)N-({1-[(1-cycloheptyl-4-piperidinyl)methyl]-4-piperidinyl}methyl)-3-(1H-imidazol-2-yl)-2-(1H-imidazol-2-ylmethyl)propanamide

TLC: Rf 0.63 (ethyl acetate:methanol:28% aqueous ammonia=8:2:0.4);

NMR (CDCl₃): δ 1.10-2.06 (m, 23H), 2.15 (d, J=6.0 Hz, 2H), 2.18-3.12 (m,13H), 3.11 (t, J=6.0 Hz, 2H), 7.00 (s, 4H), 7.68 (m, 1H).

EXAMPLE 99(2)Ethyl({4-[(8-cyclohexyl-2,8-diazaspiro[4.5]dec-2-yl)methyl]benzyl}[3-(1H-imidazol-2-yl)-2-(1H-imidazol-2-ylmethyl)propanoyl]amino)acetate

TLC: Rf 0.24 (ethyl acetate:methanol:28% aqueous ammonia=8:2:0.4);

NMR (CDCl₃): δ 1.00-2.04 (m, 16H), 1.30 (t, J=7.2 Hz, 3H), 2.25 (m, 1H),2.34 (s, 2H), 2.40-2.60 (m, 4H), 2.54 (t, J=6.9 Hz, 2H), 2.93 (dd,J=14.7, 6.9 Hz, 2H), 3.06 (dd, J=14.7 Hz, 2H), 3.44 (m, 1H), 3.55 (s,2H), 4.00 (s, 2H), 4.25 (q, J=7.2 Hz, 2H), 4.58 (s, 2H), 7.01 (s, 4H),7.03 (d, J=8.1 Hz, 2H), 7.28 (d, J=8.1 Hz, 2H).

EXAMPLE 99(3)N-{4-[(8-cyclohexyl-2,8-diazaspiro[4.5]dec-2-yl)methyl]phenyl}-3-(1H-imidazol-2-yl)-2-(1H-imidazol-2-ylmethyl)propanamide

TLC: Rf 0.23 (ethyl acetate:methanol:28% aqueous ammonia=8:2:0.4);

NMR (CDCl₃): δ 1.00-1.98 (m, 16H), 2.22-2.66 (m, 9H), 2.97 (dd, J=15.0,6.3 Hz, 2H), 3.08 (dd, J=15.0, 5.7 Hz, 2H), 3.23 (m, 1H), 3.54 (s, 2H),7.02 (s, 4H), 7.22-7.32 (m, 2H), 7.51 (d, J=8.7 Hz, 2H), 10.16 (s, 1H).

EXAMPLE 99(4)N-{4-[(8-cyclohexyl-2,8-diazaspiro[4.5]dec-2-yl)methyl]benzyl}-N-ethyl-3-(1H-imidazol-2-yl)-2-(1H-imidazol-2-ylmethyl)propanamide

TLC: Rf 0.29 (ethyl acetate:methanol:28% aqueous ammonia=8:2:0.4);

NMR (DMSO-d₆): δ 0.82-1.80 (m, 19H), 2.18-3.36 (m, 15H), 3.51 (s, 2H),3.73 (m, 1H), 4.42 (s, 2H), 6.83 (s, 4H), 6.90-7.04 (m, 2H), 7.15 (d,J=7.5 Hz, 2H).

EXAMPLE 1004-{3-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl)-2-[(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl)methyl]propoxy}benzaldehyde

To a tetrahydrofuran (2 mL) solution of the compound (120 mg) producedin Example 18 and a 4-hydroxybenzaldehyde (31 mg), triphenylphosphine(81 mg) and diethylazodicarboxylate (175 μL) were added in this order.The reaction solution was stirred at room temperature for 15 hours. Tothe reaction solution, water (20 mL) was added. The aqueous layer wasextracted twice with ethyl acetate (50 mL). The combined organic layerwas washed with saturated sodium chloride solution (50 mL) and thendried over anhydrous magnesium sulfate. After removing the anhydrousmagnesium sulfate by filtration, the filtrate was concentrated. Theresidue was purified by silica gel chromatography (n-hexane:ethylacetate=80:20→0:100→ethyl acetate:methanol: 28% aqueousammonia=100:0:0→80:20:2) to obtain the title compound (85 mg) having thefollowing physical properties.

TLC: Rf 0.31 (ethyl acetate:methanol:28% aqueous ammonia=19:1:0.1);

NMR (CDCl₃): δ-0.03 (s, 18H), 0.80-0.94 (m, 4H), 2.80-3.05 (m, 5H), 3.45(t, J=8.4 Hz, 4H), 3.90-4.35 (m, 2H), 5.10-5.30 (m, 4H), 6.80-6.98 (m,4H), 6.97 (d, J=9.0 Hz, 2H), 7.80 (d, J=9.0 Hz, 2H), 9.86 (s, 1H).

EXAMPLE 1018-[(3-methyl-2-thienyl)methyl]-2-(4-{3-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl)-2-[(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl)methyl]propoxy}benzyl)-2,8-diazaspiro[4.5]decane

Except for using the compound (85 mg) produced in Example 100 in placeof 4-(diethoxymethyl)benzaldehyde and using the compound (37 mg)produced in Example 13 in place of 8-isobutyl-2,8-diazaspiro[4.5]decane,the same operation as in Example 26 was performed to obtain the titlecompound (40 mg) having the following physical properties.

TLC: Rf 0.14 (ethyl acetate:methanol:28% aqueous ammonia=19:1:0.2);

NMR (CDCl₃): δ-0.03 (s, 18H), 0.78-0.98 (m, 4H), 1.20-3.82 (m, 30H),3.90-4.10 (m, 2H), 5.18-5.35 (m, 4H), 6.70-7.00 (m, 6H), 7.08-7.20 (m,2H), 7.44 (d, J=7.8 Hz, 2H).

EXAMPLE 1022-{4-[3-(1H-imidazol-2-yl)-2-(1H-imidazol-2-ylmethyl)propoxy]benzyl}-8-[(3-methyl-2-thienyl)methyl]-2,8-diazaspiro[4.5]decane

Except for using the compound (40 mg) produced in Example 101, the sameoperation as in Example 21 was performed to obtain the title compound (7mg) having the following physical properties.

TLC: Rf 0.36 (ethyl acetate:methanol:28% aqueous ammonia=8:2:0.2);

NMR (CDCl₃): δ 1.52-1.68 (m, 6H), 2.17 (s, 3H), 2.25-2.48 (m, 6H), 2.57(t, J=6.9 Hz, 2H), 2.60 (m, 1H), 2.75 (dd, J=14.4, 7.5 Hz, 2H), 2.89(dd, J=14.4, 4.5 Hz, 2H), 3.53 (s, 2H), 3.57 (s, 2H), 3.85 (d, J=7.2 Hz,2H), 6.77 (d, J=5.1 Hz, 1H), 6.85 (d, J=8.7 Hz, 2H), 7.02 (s, 4H), 7.11(d, J=5.1 Hz, 1H), 7.23 (d, J=8.7 Hz, 2H).

EXAMPLE 1034-{3-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl)-2-[(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl)methyl]propoxy}benzoicAcid

To a tert-butanol (2 mL) solution of the compound (50 mg) produced inExample 100, water (0.5 mL), sodium dihydrogen phosphate (11 mg),2-methyl-2-butene (46 μL) and sodium chlorite (32 mg) were added in thisorder. The reaction solution was stirred for 3 hours at roomtemperature. To the reaction solution, 1N hydrochloric acid was added soas to adjust the pH to 5. The aqueous layer was extracted twice withethyl acetate (50 mL). The combined organic layer was washed withsaturated sodium chloride solution (50 mL) and then dried over anhydrousmagnesium sulfate. After removing the anhydrous magnesium sulfate byfiltration, the filtrate was concentrated. Without purifying theresidue, the title compound (50 mg) having the following physicalproperties was obtained.

TLC: Rf 0.24 (dichloromethane:methanol:28% aqueous ammonia=8:2:0.4);

NMR (CDCl₃): δ-0.03 (s, 18H), 0.88 (t, J=8.4 Hz, 4H), 2.82 (m, 1H),3.00-3.12 (m, 2H), 3.18 (dd, J=15.6, 5.4 Hz, 2H), 3.47 (t, J=8.4 Hz,4H), 4.07 (d, J=4.5 Hz, 2H), 5.23 (d, J=11.1 Hz, 2H), 5.34 (d, J=11.1Hz, 2H), 6.94 (d, J=1.5 Hz, 2H), 7.00 (d, J=9.0 Hz, 2H), 7.07 (d, J=1.5Hz, 2H), 8.05 (d, J=9.0 Hz, 2H).

EXAMPLE 1048-cyclohexyl-2-(4-{3-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl)-2-[(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl)methyl]propoxy}benzoyl)-2,8-diazaspiro[4.5]decane

Except for using the compound (50 mg) produced in Example 103 in placeof the compound produced in Example 68 and using8-cyclohexyl-2,8-diazaspiro[4.5]decane (38 mg) in place of the compoundproduced in Example 91, the same operation as in Example 92 wasperformed to obtain the title compound (54 mg) having the followingphysical properties.

TLC: Rf 0.25 (ethyl acetate:methanol:28% aqueous ammonia=9:1:0.2);

NMR (CDCl₃): δ-0.03 (s, 18H), 0.87 (t, J=8.4 Hz, 4H), 1.00-1.92 (m,16H), 2.10-3.58 (m, 19H), 3.66 (m, 1H), 4.00-4.10 (m, 2H), 5.19 (d,J=10.8 Hz, 2H), 5.24 (d, J=10.8 Hz, 2H), 6.86 (d, J=9.0 Hz, 2H), 6.91(s, 1H), 6.94 (s, 1H), 7.45 (d, J=9.0 Hz, 2H).

EXAMPLE 1058-cyclohexyl-2-{4-[3-(1H-imidazol-2-yl)-2-(1H-imidazol-2-ylmethyl)propoxy]benzoyl}-2,8-diazaspiro[4.5]decane

Except for using the compound (54 mg) produced in Example 104 in placeof the compound produced in Example 20, the same operation as in Example21 was performed to obtain the title compound (20 mg) having thefollowing physical properties.

TLC: Rf 0.40 (ethyl acetate:methanol:28% aqueous ammonia=8:2:0.4);

NMR (CDCl₃): δ 1.00-1.95 (m, 16H), 2.18-2.78 (m, 8H), 2.87 (dd, J=14.7,4.8 Hz, 2H), 3.28-3.50 (m, 2H), 3.45-3.75 (m, 2H), 3.84 (d, J=6.9 Hz,2H), 6.80-6.90 (m, 2H), 7.02 (s, 4H), 7.46 (d, J=8.7 Hz, 2H).

EXAMPLE 1061-[4-({[tert-butyl(dimethyl)silyl]oxy}methyl)phenyl]-3-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl)-2-[(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl)methyl]-1-propanol

Except for using the compound (250 mg) produced in Example 8 in place ofthe compound produced in Example 14, the same operation as in Example 15was performed to obtain the title compound (190 mg) having the followingphysical properties.

TLC: Rf 0.54 (ethyl acetate:methanol:28% aqueous ammonia=19:1:0.2);

NMR (CDCl₃): δ-0.80-0.20 (m, 27H), 0.70-0.95 (m, 4H), 0.93 (s, 6H),2.60-3.15 (m, 5H), 3.25-3.50 (m, 4H), 4.71 (s, 2H), 4.89 (s, 2H), 4.91(d, J=3.0 Hz, 1H), 4.98 (d, J=10.8 Hz, 1H), 5.10 (d, J=10.8 Hz, 1H),6.84 (m, 1H), 6.89 (m, 1H), 6.94 (m, 1H), 6.96 (m, 1H), 7.18-7.30 (m,2H), 7.37 (d, J=7.8 Hz, 2H).

EXAMPLE 1071-[4-({[tert-butyl(dimethyl)silyl]oxy}methyl)phenyl]-3-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl)-2-[(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl)methyl]propylAcetate

Except for using the compound (90 mg) produced in Example 106 in placeof the compound produced in Example 35, the same operation as in Example36 was performed to obtain the title compound (90 mg) having thefollowing physical properties.

TLC: Rf 0.44 (ethyl acetate:methanol:28% aqueous ammonia=19:1:0.2);

NMR (CDCl₃): δ-0.80-0.20 (m, 27H), 0.75-0.90 (m, 4H), 0.93 (s, 6H),2.02-2.15 (m, 3H), 2.68-3.52 (m, 9H), 4.70 (s, 2H), 4.93 (d, J=11.1 Hz,1H), 5.00-5.15 (m, 3H), 5.92 (d, J=5.4 Hz, 1H), 6.80 (d, J=1.2 Hz, 2H),6.86 (d, J=1.8 Hz, 1H), 6.88 (d, J=1.8 Hz, 1H), 7.20-7.40 (m, 4H).

EXAMPLE 1081-[4-(hydroxymethyl)phenyl]-3-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl)-2-[(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl)methyl]propylAcetate

To the compound (90 mg) produced in Example 107, a 1M tetrabutylammoniumfluoride tetrahydrofuran solution (1 mL) was added, followed by stirringat room temperature for 2 hours. To the reaction solution, water (20 mL)was added. The aqueous layer was extracted twice with ethyl acetate (50mL). The combined organic layer was washed in turn with water (20 mL)and saturated sodium chloride solution (20 mL), and then dried overanhydrous magnesium sulfate. After removing the anhydrous magnesiumsulfate by filtration, the filtrate was concentrated. The residue waspurified by silica gel chromatography (n-hexane:ethylacetate=50:50→0:100 ethyl acetate:methanol: 28% aqueousammonia=100:0:0→100:10:1) to obtain the title compound (70 mg) havingthe following physical properties.

TLC: Rf 0.40 (ethyl acetate:methanol:28% aqueous ammonia=19:1:0.1);

NMR (CDCl₃): δ-0.04 (m, 18H), 0.82 (t, J=8.4 Hz, 4H), 2.08 (s, 3H), 2.68(dd, J=15.3, 6.9 Hz, 1H), 2.78-2.88 (m, 2H), 2.98 (dd, J=15.3, 8.7 Hz,1H), 3.10 (m, 1H), 3.28-3.42 (m, 4H), 4.66 (s, 2H), 4.93 (d, J=10.8 Hz,1H), 5.03 (s, 2H), 5.08 (d, J=10.8 Hz, 1H), 5.99 (d, J=5.1 Hz, 1H), 6.81(d, J=1.2 Hz, 2H), 6.87 (d, J=0.9 Hz, 1H), 6.88 (d, J=0.9 Hz, 1H),7.28-7.40 (m, 4H).

EXAMPLE 109(4-{3-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl)-2-[(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl)methyl]propyl}phenyl)methanol

To an ethanol solution (3 mL) of the compound (35 mg) produced inExample 108, 10% palladium carbon (20 mg) was added and the atmospherein the reaction system was replaced by hydrogen. The reaction solutionwas stirred at 50° C. for 6 hours. After removing palladium carbon byfiltering the reaction solution through Celite (trade name), thefiltrate was concentrated. Without purifying the residue, the titlecompound (20 mg) having the following physical properties was obtained.

TLC: Rf 0.22 (ethyl acetate:methanol:28% aqueous ammonia=19:1:0.1);

NMR (CDCl₃): δ 0.00 (m, 18H), 0.87 (t, J=8.4 Hz, 4H), 2.65-2.95 (m, 7H),3.41 (t, J=8.4 Hz, 4H), 4.69 (s, 2H), 5.05 (d, J=10.8 Hz, 2H), 5.17 (d,J=10.8 Hz, 2H), 6.88-6.92 (m, 2H), 6.98-7.00 (m, 2H), 7.22 (d, J=8.1 Hz,2H), 7.30 (d, J=8.1 Hz, 2H).

EXAMPLE 1104-{3-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl)-2-[(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl)methyl]propyl}benzaldehyde

Except for using the compound (140 mg) produced in Example 109 in placeof the compound produced in Example 9, the same operation as in Example10 was performed to obtain the title compound (132 mg) having thefollowing physical properties.

TLC: Rf 0.42 (ethyl acetate:methanol:28% aqueous ammonia=9:1:0.1);

NMR (CDCl₃): δ-0.05 (m, 18H), 0.82 (t, J=8.1 Hz, 4H), 2.45-3.30 (m, 7H),3.40 (t, J=8.4 Hz, 4H), 5.13 (d, J=10.5 Hz, 2H), 5.27 (d, J=10.5 Hz,2H), 6.90 (d, J=1.5 Hz, 2H), 6.98 (d, J=1.5 Hz, 2H), 7.42 (d, J=8.1 Hz,2H), 7.77 (d, J=8.1 Hz, 2H), 9.95 (s, 1H).

EXAMPLE 1118-cyclohexyl-2-(4-{3-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl)-2-[(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl)methyl]propyl}benzyl)-2,8-diazaspiro[4.5]decane

Except for using the compound (50 mg) produced in Example 110 in placeof 4-(diethoxymethyl)benzaldehyde, the same operation as in Example 26was performed to obtain (58 mg) having the following physicalproperties.

TLC: Rf 0.28 (ethyl acetate:methanol:28% aqueous ammonia=9:1:0.2);

NMR (CDCl₃): δ-0.05 (m, 18H), 0.82 (dd, J=8.7, 7.5 Hz, 4H), 1.00-2.90(m, 32H), 3.36 (dd, J=8.7, 7.5 Hz, 4H), 3.52 (s, 2H), 4.98 (d, J=10.8Hz, 2H), 5.10 (d, J=10.8 Hz, 2H), 6.86 (d, J=1.5 Hz, 2H), 6.92 (d, J=1.5Hz, 2H), 7.11 (d, J=8.1 Hz, 2H), 7.20 (d, J=8.1 Hz, 2H).

EXAMPLE 1128-cyclohexyl-2-{4-[3-(1H-imidazol-2-yl)-2-(1H-imidazol-2-ylmethyl)propyl]benzyl}-2,8-diazaspiro[4.5]decane

Except for using the compound (58 mg) produced in Example 111 in placeof the compound produced in Example 20, the same operation as in Example21 was performed to obtain the title compound (22 mg) having thefollowing physical properties.

TLC: Rf 0.22 (ethyl acetate:methanol:28% aqueous ammonia=8:2:0.4);

NMR (CDCl₃): δ 1.00-1.92 (m, 16H), 2.18-2.65 (m, 14H), 2.71 (dd, J=14.7,4.2 Hz, 2H), 3.55 (s, 2H), 7.02 (s, 4H), 7.14 (d, J=8.4 Hz, 2H),7.22-7.30 (m, 2H).

EXAMPLE 1134-{3-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl)-2-[(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl)methyl]propyl}benzoicAcid

Except for using the compound (79 mg) produced in Example 110, the sameoperation as in Example 103 was performed to obtain the title compound(79 mg) having the following physical properties.

TLC: Rf 0.31 (dichloromethane:methanol:28% aqueous ammonia=8:2:0.4);

NMR (CDCl₃): δ-0.04 (m, 18H), 0.85 (t, J=8.4 Hz, 4H), 2.90 (d, J=6.3 Hz,2H), 3.00-3.60 (m, 5H), 3.43 (t, J=8.4 Hz, 4H), 5.18-5.60 (m, 4H), 6.90(d, J=1.5 Hz, 2H), 6.98 (d, J=1.5 Hz, 2H), 7.30 (d, J=8.1 Hz, 2H), 7.89(d, J=8.1 Hz, 2H).

EXAMPLE 1148-cyclohexyl-2-(4-{3-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl)-2-[(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl)methyl]propyl}benzoyl)-2,8-diazaspiro[4.5]decane

Except for using the compound (79 mg) produced in Example 113 in placeof the compound produced in Example 100 and using8-cyclohexyl-2,8-diazaspiro[4.5]decane (41 mg) in place of the compoundproduced in Example 91, the same operation as in Example 92 wasperformed to obtain the title compound (74 mg) having the followingphysical properties.

TLC: Rf 0.29 (ethyl acetate:methanol:28% aqueous ammonia=9:1:0.2);

NMR (CDCl₃): δ-0.04 (m, 18H), 0.75-0.95 (m, 4H), 1.00-1.92 (m, 16H),2.00-3.85 (m, 20H), 4.98-5.20 (m, 4H), 6.88 (s, 2H), 6.93 (s, 2H),7.18-7.28 (m, 2H), 7.41 (d, J=7.8 Hz, 2H).

EXAMPLE 1158-cyclohexyl-2-{4-[3-(1H-imidazol-2-yl)-2-(1H-imidazol-2-ylmethyl)propyl]benzoyl}-2,8-diazaspiro[4.5]decane

Except for using the compound (74 mg) produced in Example 114 in placeof the compound produced in Example 20, the same operation as in Example21 was performed to obtain the title compound (28 mg) having thefollowing physical properties.

TLC: Rf 0.42 (ethyl acetate:methanol:28% aqueous ammonia=8:2:0.4);

NMR (CDCl₃): δ 1.00-1.95 (m, 16H), 2.18-2.65 (m, 12H), 3.25-3.55 (m,2H), 3.45-3.75 (m, 2H), 7.02 (s, 4H), 7.18-7.25 (m, 2H), 7.42 (d, J=7.8Hz, 2H).

BIOLOGICAL EXAMPLES

Efficacy of the compound of the present invention, for example the factthat the compound of the present invention has CXCR4 antagonisticactivity, has been demonstrated by the following experiment.

A measuring method of the present invention was modified to improveaccuracy and/or sensitivity of the measurement for evaluating thecompound of the present invention. The detailed experimental methods areshown bellow.

As mentioned above, a more direct procedure is a screening a compoundthat prevents for HIV from binding to CXCR4, which is a receptor on CD4+cell, on an assay system using HIV viruses. However, using HIV virusesfor a large-scale screening is not practical due to its difficulthandling. On the other hand, both of T cell-directed (X4) HIV-1 andSDF-1 bind to CXCR4 and therefore CXCR4 binding sites at both ofHIV-side and SDF-1-side as well as SDF-1- and HIV-binding sites at theCXCR4 side may presumably have any common characteristics. Thus, to finda compound inhibiting absorption of HIV viruses to a cell that is adifferent mechanism from those of pre-existing anti-AIDS drugs (reversetranscriptase inhibitors and protease inhibitors), an assay system usingan endogenous ligand for CXCR4, SDF-1 instead of HIV may be available.

Specifically, as a system of screening a compound that inhibits thebinding between SDF-1 and CXCR4, for example a system of measuring thebinding between iodine-labeled SDF-1 and a human T cell strain in whichCXCR4 is known to be expressed is operable. The identical idea ispossible since macrophage (R5) HIV and RANTES, MIP-1α, and MIP-1β allbind to CCR5.

TEST METHODS Test Example 1 Study for Inhibition of Binding Human SDF-1to CEM Cells

To human T cell strain CEM cells in a binding buffer (containing HEPESand BSA), the test compound and ¹²⁵I-SDF-1 (NEN) were added and themixture was incubated at 4° C. for 60 minutes. The reacted CEM cellswere rapidly filtrated with a GF/B membrane filter plate (Packard) toadsorb. The plate was washed with PBS three times and then dried.Microscint+20 (Packard) was added thereto. An amount of theradioactivity bound to the CEM cells was measured using Top Count(Packard) and inhibition (%) of the test compound was calculatedaccording to the following equation:

Inhibition={(Et−Ea)/(Et−Ec)}×100

wherein

Et: amount of radioactivity when the test compound is not added,

Ec: amount of radioactivity when non-radioactive SDF-1 (Pepro Tech) isadded in an amount of 1000 times as much as ¹²⁵I-SDF-1 as a testcompound, and

Ea: amount of radioactivity when the test compound is added.

All compounds of the present invention shown in the Example exhibitedinhibition of 50% or more in a concentration of 10 μM. For example, IC₅₀value for compound 14 was 11 nM.

FORMULATION EXAMPLES Formulation Example 1

3-(1H-imidazol-2-yl)-2-(1H-imidazol-2-ylmethyl)-1-[4-({8-[(3-methyl-2-thienyl)methyl]-2,8-diazaspiro[4.5]dec-2-yl}methyl)phenyl]propan-1-one(200 g), calcium carboxymethyl cellulose (disintegrant, 20.0 g),magnesium stearate (lubricants, 10.0 g) and microcrystalline cellulose(870 g) were mixed by a conventional method and then compressed toobtain 10,000 tablets each containing 20 mg of an active ingredient.

Formulation Example 2

3-(1H-imidazol-2-yl)-2-(1H-imidazol-2-ylmethyl)-1-[4-({8-[(3-methyl-2-thienyl)methyl]-2,8-diazaspiro[4.5]dec-2-yl}methyl)phenyl]propan-1-one(100 g), mannitol (2 kg) and distilled water (50 L) were mixed by aconventional method and filtered with a dust filter, and then eachampoule was filled with 5 mL of the obtained mixture and subjected toheat sterilization in an autoclave to obtain 10,000 ampoules eachcontaining 10 mg of an active ingredient.

INDUSTRIAL APPLICABILITY

The compound of the present invention has CXCR4 antagonistic activityand is therefore useful as a preventive and/or therapeutic agent forCXCR4-mediated diseases. Accordingly, the compound of the presentinvention can be available as a drug. For example, the compound of thepresent invention is useful as a preventive and/or therapeutic agent forinflammatory and immune diseases (for example, rheumatoid arthritis,arthritis, retinopathy, pulmonary fibrosis, rejection of transplantedorgan, etc.), allergic diseases, infections (for example, humanimmunodeficiency virus infection, acquired immunodeficiency syndrome,etc.), psychoneurotic diseases, cerebral diseases, cardiovasculardisease, metabolic diseases, and cancerous diseases (for example,cancer, cancer metastasis, etc.), or an agent for regeneration therapy.

1. A compound represented by formula (I):

wherein A¹ and A² each independently represents a group having a basicgroup; B¹ and B² each independently represents a bond, or a spacerhaving a main chain of 1 to 4 atom(s); E represents a spacer having amain chain of 1 to 10 atom(s); L represents a bond, or a spacer having amain chain of 1 to 4 atom(s); J represents (1) an aliphatic hydrocarbongroup which may be substituted with a group having a basic group, andalso may have a substituent(s), (2) a monocyclic or condensed cyclicgroup which may be substituted with a group having a basic group, andalso may have a substituent(s), (3) a spiro-bound cyclic group which maybe substituted with a group having a basic group, and also may have asubstituent(s), or (4) a bridged cyclic group which may be substitutedwith a group having a basic group, and also may have a substituent(s); Grepresents G^(A) or G^(1A)-G^(2A)-G^(3A); G^(A) represents a bond, acarbon atom which may have a substituent(s), or a nitrogen atom whichmay have a substituent; G^(1A) represents a carbon atom which may have asubstituent(s); G^(2A) represents a carbon atom which may have asubstituent(s), a nitrogen atom which may have a substituent, anoptionally oxidized sulfur atom or an oxygen atom; G^(3A) represents abond, or a carbon atom which may have a substituent(s); and R representsa hydrogen atom, or a substituent), a salt thereof, a solvate thereof,or a prodrug thereof.
 2. The compound according to claim 1, wherein R isa hydrogen atom, a salt thereof, a solvate thereof, or a prodrugthereof.
 3. The compound according to claim 1, wherein A¹ and A² eachindependently represents a nitrogen-containing heterocyclic ring whichmay have a substituent(s), a salt thereof, a solvate thereof, or aprodrug thereof.
 4. The compound according to claim 3, wherein thenitrogen-containing heterocyclic ring is an imidazole ring, abenzoimidazole ring, or a pyridine ring, a salt thereof, a solvatethereof, or a prodrug thereof.
 5. The compound according to claim 1,wherein the spacer having a main chain of 1 to 4 atom(s) represented byB¹ and B² is —CH₂—, a salt thereof, a solvate thereof, or a prodrugthereof.
 6. The compound according to claim 1, wherein G is —CO—, —CH₂—,—CH(OH)—, or —NH—, a salt thereof, a solvate thereof, or a prodrugthereof.
 7. The compound according to claim 1, wherein E is a benzenering or a cyclohexane ring, a salt thereof, a solvate thereof, or aprodrug thereof.
 8. The compound according to claim 1, wherein L is—CH₂— or —CH₂—NH-(provided that a nitrogen atom is bonded to J), a saltthereof, a solvate thereof, or a prodrug thereof.
 9. The compoundaccording to claim 1, wherein J is (3) a spiro-bound cyclic group whichmay be substituted with a group having a basic group, and also may havea substituent(s), or (4) a bridged cyclic group which may be substitutedwith a group having a basic group, and also may have a substituent(s), asalt thereof, a solvate thereof, or a prodrug thereof.
 10. The compoundaccording to claim 9, wherein J is a spiro-bound polycyclic heterocyclicring or bridged polycyclic heterocyclic ring which has at least onenitrogen atom, and also may have an oxygen atom and/or an optionallyoxidized sulfur atom, and which may be substituted with a group having abasic group, and also may have a substituent(s), a salt thereof, asolvate thereof, or a prodrug thereof.
 11. The compound according toclaim 9, wherein the spiro-bound polycyclic heterocyclic ring or bridgedpolycyclic heterocyclic ring which has at least one nitrogen atom, andalso may have an oxygen atom and/or an optionally oxidized sulfur atomis:

wherein the nitrogen atom of —NH— may have a substituent(s), a saltthereof, a solvate thereof, or a prodrug thereof.
 12. The compoundaccording to claim 10, wherein the spiro-bound polycyclic heterocyclicring is a 7- to 15-membered spiro-bound bicyclic heterocyclic ring whichconsists of (i) a monocyclic ring composed of at least one nitrogen atomand carbon atoms and/or (ii) a monocyclic ring composed of at least onenitrogen atom, one oxygen atom and carbon atoms, a salt thereof, asolvate thereof, or a prodrug thereof.
 13. The compound according toclaim 12, wherein the 7- to 15-membered spiro-bound bicyclicheterocyclic ring is:

wherein the nitrogen atom of —NH— may have a substituent(s), a saltthereof, a solvate thereof, or a prodrug thereof.
 14. The compoundaccording to claim 1, wherein formula (I) is formula (I-1):

wherein ring A^(1A) and ring A^(2A) each independently represents animidazole ring which may have a substituent(s), a benzoimidazole ringwhich may have a substituent(s), or a pyridine ring which may have asubstituent(s), G¹ represents —CO—, —CH₂—, —CH(OH)—, or —NH—, ring E¹represents a 3- to 8-membered monocyclic group which may have asubstituent(s), and other symbols are as defined in claim 1, a saltthereof, a solvate thereof, or a prodrug thereof.
 15. The compoundaccording to claim 14, wherein

wherein L^(A) represents (a)-(an aliphatic hydrocarbon having 1 to 3carbon atoms(s) which may have a substituent(s))-(a nitrogen atom whichmay have a substituent)-, or (b) a divalent aliphatic hydrocarbon having1 to 4 carbon atoms(s) which may have a substituent(s), (a) when L^(A)is -(an aliphatic hydrocarbon having 1 to 3 carbon atoms(s) which mayhave a substituent(s))-(a nitrogen atom which may have a substituent)-,ring J¹ represents a 3- to 10-membered monocyclic or bicyclicheterocyclic ring composed of (i) a C3-10 monocyclic or bicycliccarbocyclic ring, or (ii) a 3- to 10-membered monocyclic or bicyclicheterocyclic ring composed of a carbon atom(s), an oxygen atom(s) and/oran optionally oxidized sulfur atom(s), (b) when L^(A) is a divalentaliphatic hydrocarbon having 1 to 4 carbon atom(s) which may have asubstituent(s), ring J¹ represents a 3- to 10-membered monocyclic orbicyclic heterocyclic ring which has at least one nitrogen atom, andalso may have an oxygen atom(s) and/or an optionally oxidized sulfuratom(s), ring J² represents (i) a C3-10 monocyclic or bicycliccarbocyclic ring substituted with a group having a basic group, (ii) a3- to 10-membered monocyclic or bicyclic heterocyclic ring composed of acarbon atom(s), an oxygen atom(s) and/or an optionally oxidized sulfuratom(s), which is substituted with a group having a basic group, or(iii) a 3- to 10-membered monocyclic or bicyclic heterocyclic ring whichhas at least one nitrogen atom and also may have an oxygen atom(s) or anoptionally oxidized sulfur atom(s), and also may be substituted with agroup having a basic group, ring J¹ and ring J² may have 1 to 8substituent(s) on the substitutable position and, when two or moresubstituents are present, plural substituents may be the same ordifferent, wherein a nitrogen atom which may have a substituent in L^(A)is bonded to ring J¹, a salt thereof, a solvate thereof, or a prodrugthereof.
 16. The compound according to claim 15, wherein

wherein L^(A) is as defined in claim 15, provided that L^(A) may bebonded to the nitrogen atom of —NH— and the nitrogen atom of —NH— mayhave a substituent(s), a salt thereof, a solvate thereof, or a prodrugthereof.
 17. The compound according to claim 1, wherein

wherein L^(A) is as defined in claim 15, provided that L^(A) may bebonded to the nitrogen atom of —NH— and the nitrogen atom of —NH— mayhave a substituent(s), a salt thereof, a solvate thereof, or a prodrugthereof.
 18. The compound according to claim 1, wherein formula (I) isformula (I-4):

wherein ring E² represents a benzene ring which may have asubstituent(s), a cyclohexane ring which may have a substituent(s), acyclopentane ring which may have a substituent(s), a pyrrolidine ringwhich may have a substituent(s), or a piperidine ring which may have asubstituent(s); R^(C) represents (1) a hydrogen atom, (2) cyano group,(3) a carboxyl group which may be protected with a protective group, (4)a hydroxyl group which may be protected with a protective group, (5) aC1-4 alkyl group which may be substituted with a hydroxyl group whichmay be protected with a protective group, or (6) an amino group whichmay be protected with a protective group; and -L^(B)-J^(B) represents(a) L^(1B)-J^(1B) wherein L^(1B) represents —CH₂—NH— or —CO—NH— whereinthe nitrogen atom is bonded to J^(1B), and J^(1B) represents a C4-7monocyclic carbocyclic ring substituted with a mono- or di-substitutedamino group, or (b)

wherein L^(2B) represents a carbon atom which may have a substituent(s)and R¹ represents a hydrogen atom or a substituent), and other symbolsare as defined in claim 1 and claim 14, a salt thereof, a solvatethereof, or a prodrug thereof.
 19. The compound according to claim 18,wherein the protective group is a C1-4 alkyl group which may besubstituted with an oxo group, a salt thereof, a solvate thereof, or aprodrug thereof.
 20. The compound according to claim 18, wherein thesubstituent of the carbon atom which may have a substituent(s)represented by G^(1A) is absent, a hydroxyl group, an oxo group, or aC1-4 alkyl group, a salt thereof, a solvate thereof, or a prodrugthereof.
 21. The compound according to claim 18, wherein G^(2A) is anitrogen atom which may have a substituent and G^(3A) is a carbon atomwhich may have a substituent(s), a salt thereof, a solvate thereof, or aprodrug thereof.
 22. The compound according to claim 21, wherein thesubstituent of the carbon atom which may have a substituent(s)represented by G^(2A) is (1) absent, (2) a C1-4 alkyl group, (3) a C1-4alkyl group substituted with a hydroxyl group which may be protectedwith a protective group, (4) a C1-4 alkyl group substituted with anamino group which may be protected with a protective group, (5) a C1-4alkyl group substituted with a carboxyl group which may be protectedwith a protective group, or (6) a C1-4 alkyl group substituted with apyrrolidine ring, a piperidine ring or a morpholine ring, a saltthereof, a solvate thereof, or a prodrug thereof.
 23. The compoundaccording to claim 22, wherein the protective group is a C1-4 alkylgroup which may be substituted with an oxo group, a salt thereof, asolvate thereof, or a prodrug thereof.
 24. The compound according toclaim 21, wherein the substituent of the carbon atom which may have asubstituent(s) represented by G^(3A) is absent, a C1-4 alkyl group, ahydroxyl group or an oxo group, a salt thereof, a solvate thereof, or aprodrug thereof.
 25. The compound according to claim 18, wherein-L^(B)-J^(B) is (a) -L^(1B)-J^(1B) (symbols in the group are as definedin claim 18), a salt thereof, a solvate thereof, or a prodrug thereof.26. The compound according to claim 18, wherein -L^(B)-J^(B) is (b)

wherein symbols are as defined in claim 18, a salt thereof, a solvatethereof, or a prodrug thereof.
 27. The compound according to claim 18,wherein formula (I) is formula (I-4-a):

wherein G^(3B) represents —CH₂— or —CO—, R^(1C) represents a hydrogenatom, a cyano group, a C1-4 alkyl group substituted with a hydroxylgroup, or a C1-4 alkyl group substituted with an acetyloxy group, R²represents a hydrogen atom, or a hydroxyethyl, acetyl, methoxyethyl,pyrrolidinylethyl, morpholinylethyl, hydroxymethylcarbonyl,dimethylaminoethyl or acetylaminoethyl group, and R³ represents a C1-4alkyl group, a C5-7 saturated monocyclic carbocyclic ring or a(3-methyl-2-thienyl)methyl group, a salt thereof, a solvate thereof, ora prodrug thereof.
 28. The compound according to claim 1, whereinformula (I) is formula (I-5):

wherein R⁴ and R⁵ represent a hydrogen atom or a substituent and othersymbols are as defined in claim 14 and claim 18, a salt thereof, asolvate thereof, or a prodrug thereof.
 29. The compound according toclaim 1, wherein formula (I) is formula (I-6):

wherein R⁶ represents a hydrogen atom or a substituent and other symbolsare as defined in claim 14 and claim 18, a salt thereof, a solvatethereof, or a prodrug thereof.
 30. The compound according to claim 1,which is2-{4-[3-(1H-imidazol-2-yl)-2-(1H-imidazol-2-ylmethyl)propoxy]benzyl}-8-[(3-methyl-2-thienyl)methyl]-2,8-diazaspiro[4.5]decane,N-[3-(1H-imidazol-2-yl)-2-(1H-imidazol-2-ylmethyl)propyl]-N-[4-({8-[(3-methyl-2-thienyl)methyl]-2,8-diazaspiro[4.5]dec-2-yl}methyl)benzyl]acetoamide,8-cyclohexyl-2-{4-[3-(1H-imidazol-2-yl)-2-(1H-imidazol-2-ylmethyl)propyl]benzyl}-2,8-diazaspiro[4.5]decane,3-({4-[(8-cyclohexyl-2,8-diazaspiro[4.5]dec-2-yl)methyl]benzyl}amino)-2,2-bis(1H-imidazol-2-ylmethyl)-1-propanol,2-{{4-[(8-cyclohexyl-2,8-diazaspiro[4.5]dec-2-yl)methyl]benzyl}[3-(1H-imidazol-2-yl)-2-(1H-imidazol-2-ylmethyl)propyl]amino}ethanol,N-[2-cyano-3-(1H-imidazol-2-yl)-2-(1H-imidazol-2-ylmethyl)propyl]-N-{4-[(8-cyclohexyl-2,8-diazaspiro[4.5]dec-2-yl)methyl]benzyl}acetoamide,N-[3-(1H-imidazol-2-yl)-2-(1H-imidazol-2-ylmethyl)propyl]-4-[(8-isobutyl-2,8-diazaspiro[4.5]dec-2-yl)methyl]benzamide,N-[3-(1H-imidazol-2-yl)-2-(1H-imidazol-2-ylmethyl)propyl]-4-[(8-isobutyl-2,8-diazaspiro[4.5]dec-2-yl)methyl]-N-(2-methoxyethyl)benzamide,N-[3-(1H-imidazol-2-yl)-2-(1H-imidazol-2-ylmethyl)propyl]-4-[(8-isobutyl-2,8-diazaspiro[4.5]dec-2-yl)methyl]-N-[2-(1-pyrrolidinyl)ethyl]benzamide,2-hydroxy-N-[3-(1H-imidazol-2-yl)-2-(1H-imidazol-2-ylmethyl)propyl]-N-{4-[(8-isobutyl-2,8-diazaspiro[4.5]dec-2-yl)methyl]benzyl}acetoamide,N-[3-hydroxy-2,2-bis(1H-imidazol-2-ylmethyl)propyl]-N-{4-[(8-isobutyl-2,8-diazaspiro[4.5]dec-2-yl)methyl]benzyl}acetoamide,N-[2-(dimethylamino)ethyl]-N-[3-(1H-imidazol-2-yl)-2-(1H-imidazol-2-ylmethyl)propyl]-4-[(8-isobutyl-2,8-diazaspiro[4.5]dec-2-yl)methyl]benzamide,N-(2-acetoamideethyl)-N-[3-(1H-imidazol-2-yl)-2-(1H-imidazol-2-ylmethyl)propyl]-4-[(8-isobutyl-2,8-diazaspiro[4.5]dec-2-yl)methyl]benzamide,N-[3-(1H-imidazol-2-yl)-2-(1H-imidazol-2-ylmethyl)propyl]-4-[(8-isobutyl-2,8-diazaspiro[4.5]dec-2-yl)methyl]-N-[2-(4-morpholinyl)ethyl]benzamide,or3-({4-[(8-cyclohexyl-2,8-diazaspiro[4.5]dec-2-yl)methyl]benzoyl}amino)-2,2-bis(1H-imidazol-2-ylmethyl)propylacetate, a salt thereof, a solvate thereof, or a prodrug thereof.
 31. Apharmaceutical composition comprising a compound represented by formula(I) according to claim 1, a salt thereof, a solvate thereof, or aprodrug thereof.
 32. The pharmaceutical composition according to claim31, which is a CXCR4 antagonist.
 33. The pharmaceutical compositionaccording to claim 31, which is preventive and/or therapeutic agent forCXCR4-mediated diseases, or an agent for regeneration therapy.
 34. Thepharmaceutical composition according to claim 33, wherein theCXCR4-mediated disease is human immunodeficiency virus infection,acquired immunodeficiency syndrome, cancer, cancer metastasis,rheumatoid arthritis, arthritis, retinopathy, pulmonary fibrosis orrejection of transplanted organ, or the agent for regeneration therapyis an agent for transplantation medical treatment.
 35. Thepharmaceutical composition according to claim 33, wherein theCXCR4-mediated disease is human immunodeficiency virus infection.
 36. Amedicament comprising a compound represented by formula (I) according toclaim 1, a salt thereof, a solvate thereof, or a prodrug thereof, andone or more kinds selected from reverse transcriptase inhibitor,protease inhibitor, CCR2 antagonist, CCR3 antagonist, CCR4 antagonist,CCR5 antagonist, CXCR4 antagonist, HIV integrase inhibitor, fusioninhibitor, CD4 antagonist, antibody against surface antigen of HIV,Short Interfering RNA targeting a HIV-related factor, and vaccine of HIV37. A method for antagonizing CXCR4 in a mammal, comprisingadministering an effective dosage of a compound represented by formula(I) according to claim 1, a salt thereof, a solvate thereof, or aprodrug thereof to the mammal.
 38. A method of prevention and/ortreatment for CXCR4-mediated diseases in a mammal, comprisingadministering an effective dosage of a compound represented by formula(I) according to claim 1, a salt thereof, a solvate thereof, or aprodrug thereof to the mammal.
 39. (canceled)
 40. (canceled)